Herbicidal compounds

Abstract

Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially as herbicides. ##STR00001##

Claims

1. A compound of Formula (I) or an agronomically acceptable salt or zwitterionic species thereof: ##STR00431## wherein R.sup.1 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6haloalkyl, —OR.sup.7, —OR.sup.15a, —N(R.sup.6)S(O).sub.2R.sup.15, —N(R.sup.6)C(O)R.sup.15, —N(R.sup.6)C(O)OR.sup.15, —N(R.sup.6)C(O)NR.sup.16R.sup.17, —N(R.sup.6)CHO, —N(R.sup.7a).sub.2 and —S(O).sub.rR.sup.15; R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; and wherein when R.sup.1 is selected from the group consisting of —OR.sup.7, —OR.sup.15a, —N(R.sup.6)S(O).sub.2R.sup.15, —N(R.sup.6)C(O)R.sup.15, —N(R.sup.6)C(O)OR.sup.15, —N(R.sup.6)C(O)NR.sup.16R.sup.17, —N(R.sup.6)CHO, —N(R.sup.7a).sub.2 and —S(O).sub.rR.sup.15, R.sup.2 is selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form a C.sub.3-C.sub.6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; Q is (CR.sup.1aR.sup.2b).sub.m, m is 0, 1, 2 or 3; each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, —OH, —OR.sup.7, —OR.sup.15a, —NH.sub.2, —NHR.sup.7, —NHR.sup.15a, —N(R.sup.6)CHO, —NR.sup.7bR.sup.7c and —S(O).sub.rR.sup.15; or each R.sup.1a and R.sup.2b together with the carbon atom to which they are attached form a C.sub.3-C.sub.6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O).sub.rR.sup.15, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.6cycloalkyl and —N(R.sup.6).sub.2; each R.sup.6 is independently selected from hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.7 is independently selected from the group consisting of C.sub.1-C.sub.6alkyl, —S(O).sub.2R.sup.15, —C(O)R.sup.15, —C(O)OR.sup.15 and —C(O)NR.sup.16R.sup.17; each R.sup.7a is independently selected from the group consisting of —S(O).sub.2R.sup.15, —C(O)R.sup.15, —C(O)OR.sup.15—C(O)NR.sup.16R.sup.17 and —C(O)NR.sup.6R.sup.15a; R.sup.7b and R.sup.7c are independently selected from the group consisting of C.sub.1-C.sub.6alkyl, —S(O).sub.2R.sup.15, —C(O)R.sup.15, —C(O)OR.sup.15, —C(O)NR.sup.16R.sup.17 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; or R.sup.7b and R.sup.7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and A is a 6-membered heteroaryl, which comprises 1, 2, 3 or 4 nitrogen atoms and wherein the heteroaryl may be optionally substituted by 1, 2, 3 or 4 R.sup.8 substituents, which may be the same or different, and wherein when A is substituted by 1 or 2 substituents, each R.sup.8 is independently selected from the group consisting of halogen, nitro, cyano, —NH.sub.2, —NHR.sup.7, —N(R.sup.7).sub.2, —OH, —OR.sup.7, —S(O).sub.rR.sup.15, —NR.sup.6S(O).sub.2R.sup.15, —C(O)OR.sup.10, —C(O)R.sup.15, —C(O)NR.sup.16R.sup.17, —S(O).sub.2NR.sup.16R.sup.17, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.3-C.sub.6cycloalkoxy, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl-, hydroxyC.sub.1-C.sub.6alkyl-, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkoxy-, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxyC.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6alkenyloxy, C.sub.3-C.sub.6alkynyloxy, N—C.sub.3-C.sub.6cycloalkylamino, —C(R.sup.6)═NOR.sup.6, phenyl, a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; and wherein when A is substituted by 3 or 4 substituents, each R.sup.8 is independently selected from the group consisting of halogen, —NH.sub.2, —NHR.sup.7, —N(R.sup.7).sub.2, —OH, —OR.sup.7, —C(O)NR.sup.16R.sup.17, —S(O).sub.2NR.sup.16R.sup.17, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; and each R.sup.9 is independently selected from the group consisting of halogen, cyano, —OH, —N(R.sup.6).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; X is selected from the group consisting of C.sub.3-C.sub.6cycloalkyl, phenyl, a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R.sup.9 substituents, and wherein the aforementioned CR.sup.1R.sup.2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties; n is 0 or 1; Z is selected from the group consisting of —C(O)OR.sup.10, —CH.sub.2OH, —CHO, —C(O)NHOR.sup.11, —C(O)NHCN, —OC(O)NHOR.sup.11, —OC(O)NHCN, —NR.sup.6C(O)NHOR.sup.11, —NR.sup.6C(O)NHCN, —C(O)NHS(O).sub.2R.sup.12, —OC(O)NHS(O).sub.2R.sup.12, —NR.sup.6C(O)NHS(O).sub.2R.sup.12, —S(O).sub.2OR.sup.10, —OS(O).sub.2OR.sup.10, —NR.sup.6S(O).sub.2OR.sup.10, —NR.sup.6S(O)OR.sup.10, —NHS(O).sub.2R.sup.14, —S(O)OR.sup.10, —OS(O)OR.sup.10, —S(O).sub.2NHCN, —S(O).sub.2NHC(O)R.sup.18, —S(O).sub.2NHS(O).sub.2R.sup.12, —OS(O).sub.2NHCN, —OS(O).sub.2NHS(O).sub.2R.sup.12, —OS(O).sub.2NHC(O)R.sup.18, —NR.sup.6S(O).sub.2NHCN, —NR.sup.6S(O).sub.2NHC(O)R.sup.18, —N(OH)C(O)R.sup.15, —ONHC(O)R.sup.15, —NR.sup.6S(O).sub.2NHS(O).sub.2R.sup.12, —P(O)(R.sup.13)(OR.sup.10), —P(O)H(OR.sup.10), —OP(O)(R.sup.13)(OR.sup.10), —NR.sup.6P(O)(R.sup.13)(OR.sup.10) and tetrazole; R.sup.10 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.11 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.12 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, —OH, —N(R.sup.6).sub.2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.13 is selected from the group consisting of —OH, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy and phenyl; R.sup.14 is C.sub.1-C.sub.6haloalkyl; R.sup.15 is selected from the group consisting of C.sub.1-C.sub.6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; or R.sup.16 and R.sup.17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and R.sup.18 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, —N(R.sup.6).sub.2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; and r is 0, 1 or 2.

2. The compound according to claim 1, wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl.

3. The compound according to claim 1, wherein each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, —OH and —NH.sub.2.

4. The compound according to claim 1, wherein m is 1 or 2.

5. The compound according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy.

6. The compound according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are hydrogen.

7. The compound according to claim 1, wherein A is selected from the group consisting of formula A-I to A-VII below ##STR00432## wherein the jagged line defines the point of attachment to the remaining part of a compound of Formula (I), p is 0, 1 or 2 and R.sup.8 is as defined in claim 1.

8. The compound according to claim 1, wherein A is selected from the group consisting of formula A-I to A-V below ##STR00433## wherein the jagged line defines the point of attachment to the remaining part of a compound of Formula (I), p is 0, 1, or 2 and R.sup.8 is as defined in claim 1.

9. The compound according to claim 1, wherein when A is substituted by 1 or 2 substituents, each R.sup.8 is independently selected from the group consisting of halogen, nitro, cyano, —NH.sub.2, —NHR.sup.7, —N(R.sup.7).sub.2, —OH, —OR.sup.7, —S(O).sub.rR.sup.15, —NR.sup.6S(O).sub.2R.sup.15, —C(O)OR.sup.10, —C(O)R.sup.15, —C(O)NR.sup.16R.sup.17, —S(O).sub.2NR.sup.16R.sup.17, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl.

10. The compound according to claim 1, wherein when A is substituted by 1 or 2 substituents, each R.sup.8 is independently selected from the group consisting of chloro, fluoro, cyano, —NH.sub.2, —N(Me).sub.2, —OMe, —S(O).sub.2Me, —C(O)NHMe, —C(O)N(Me).sub.2, methyl and trifluoromethyl.

11. The compound according to claim 7, wherein A is selected from the group consisting of formula A-I to A-V and p is 0.

12. The compound according to claim 1, wherein Z is selected from the group consisting of —C(O)OR.sup.10, —C(O)NHS(O).sub.2R.sup.12, —S(O).sub.2OR.sup.10, and —P(O)(R.sup.13)(OR.sup.10).

13. The compound according to claim 1, wherein Z is —C(O)OH or —S(O).sub.2OH.

14. The compound according to claim 1, wherein n is 0.

15. An agrochemical composition comprising a herbicidally effective amount of a compound of Formula (I) as defined in claim 1 and an agrochemically-acceptable diluent or carrier.

16. A method of controlling plant growth, comprising applying a compound of Formula (T) as defined in claim 1, to the plants or to a locus thereof.

17. A process for preparing a compound of formula (I) as defined in claim 1, comprising: (i) either (a) reacting a compound of formula (H)
A-Hal  formula (H) wherein A is as defined in claim 1 and Hal is a halogen, triflate, mesylate, or tosylate, with a compound of formula (J) ##STR00434## wherein R.sup.3, R.sup.4 and R.sup.5 are as defined in claim 1 and M′ is an organostannane or an organoborane, in the presence of a palladium catalyst, to give a compound of formula (X) ##STR00435## or (b) reacting a compound of formula (K) ##STR00436## wherein R.sup.3, R.sup.4 and R.sup.5 are as defined in claim 1 and Hal is a halogen triflate, mesylate, or tosylate, with a compound of formula (L)
A-M′  formula (L) wherein A is as defined in-claim 1 and M′ is an organostannane or an organoborane, in the presence of a palladium catalyst, to give a compound of formula (X); (ii) reacting a compound of formula (X) with an alkylating agent of formula (W) ##STR00437## wherein R.sup.1, R.sup.2, Q, X, Z and n are as defined in claim 1 and LG is a leaving group, in an inert solvent or mixture of inert solvents, at a temperature of from −78° C. to 150° C., to give a compound of formula (I); (iii) optionally, partially or fully hydrolysing a compound of formula (I) in the presence of a acid.

18. The process of claim 17, wherein for a compound of formula (J), M′ is tributylstannane.

19. The process of claim 17, wherein the compound of formula (X) is selected from the group consisting of 2-pyridazin-4-ylpyrimidine, 4-pyridazin-4-ylpyrimidine, 3-pyridazin-4-ylpyridazine, 2-pyridazin-4-ylpyrazine and 4-pyridazin-4-ylpyridazine.

20. A compound selected from the group consisting of 2-pyridazin-4-ylpyrimidine, 3-pyridazin-4-ylpyridazine and 2-pyridazin-4-ylpyrazine.

21. A process, comprising: (a) reacting a compound of formula (H)
A-Hal  formula (H) wherein A is as defined in claim 1 and Hal is a halogen, triflate, mesylate, or tosylate, with a compound of formula (J) ##STR00438## wherein R.sup.3, R.sup.4 and R.sup.5 are as defined in claim 1 and M′ is an organostannane or an organoborane, in the presence of a palladium catalyst, to give a compound of formula (X) ##STR00439##

22. A process for preparing a compound of formula (I) as defined in claim 1, comprising: reacting a compound of formula (X) ##STR00440## where A, R.sup.3, R.sup.4 and R.sup.5 are as defined in claim 1 with an alkylating agent of formula (W) ##STR00441## wherein R.sup.1, R.sup.2, Q, X, Z and n are as defined in claim 1 and LG is a leaving group, in an inert solvent or mixture of inert solvents, at a temperature of from −78° C. to 150° C., to give a compound of formula (I) as defined in claim 1.

23. A compound selected from the group consisting of: ##STR00442##

24. The compound of claim 23, wherein the compound is ##STR00443##

25. The compound of claim 23, wherein the compound is ##STR00444##

26. The compound of claim 23, wherein the compound is ##STR00445##

27. The compound of claim 23, wherein the compound is ##STR00446##

28. The compound of claim 23, wherein the compound is ##STR00447##

29. The compound of claim 23, wherein the compound is ##STR00448##

Description

EXAMPLES

(1) The Examples which follow serve to illustrate, but do not limit, the invention.

FORMULATION EXAMPLES

(2) TABLE-US-00004 Wettable powders a) b) c) active ingredients 25%  50% 75% sodium lignosulfonate 5%  5% — sodium lauryl sulfate 3% —  5% sodium —  6% 10% diisobutylnaphthalenesulfonate phenol polyethylene glycol ether —  2% — (7-8 mol of ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62%  27% —

(3) The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.

(4) TABLE-US-00005 Emulsifiable concentrate active ingredients 10% octylphenol polyethylene glycol  3% ether (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate  3% castor oil polyglycol ether (35 mol of ethylene oxide)  4% Cyclohexanone 30% xylene mixture 50%

(5) Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

(6) TABLE-US-00006 Dusts a) b) c) Active ingredients  5%  6%  4% Talcum 95% — — Kaolin — 94% — mineral filler — — 96%

(7) Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill.

(8) TABLE-US-00007 Extruder granules Active ingredients 15% sodium lignosulfonate  2% carboxymethylcellulose  1% Kaolin 82%

(9) The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.

(10) TABLE-US-00008 Coated granules Active ingredients 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89% 

(11) The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.

(12) TABLE-US-00009 Suspension concentrate active ingredients 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide)  6% Sodium lignosulfonate 10% carboxymethylcellulose  1% silicone oil (in the form of a 75% emulsion in water)  1% Water 32%

(13) The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.

(14) Slow Release Capsule Suspension

(15) 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.

(16) The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.

(17) The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

List of Abbreviations

(18) Boc=tert-butyloxycarbonyl

(19) br=broad

(20) CDCl.sub.3=chloroform-d

(21) CD.sub.3OD=methanol-d

(22) ° C.=degrees Celsius

(23) D.sub.2O=water-d

(24) DCM=dichloromethane

(25) d=doublet

(26) dd=double doublet

(27) dt=double triplet

(28) DMSO=dimethylsulfoxide

(29) EtOAc=ethyl acetate

(30) h=hour(s)

(31) HCl=hydrochloric acid

(32) HPLC=high-performance liquid chromatography (description of the apparatus and the methods used for HPLC are given below)

(33) m=multiplet

(34) M=molar

(35) min=minutes

(36) MHz=megahertz

(37) mL=millilitre

(38) mp=melting point

(39) ppm=parts per million

(40) q=quartet

(41) quin=quintet

(42) rt=room temperature

(43) s=singlet

(44) t=triplet

(45) THE=tetrahydrofuran

(46) LC/MS=Liquid Chromatography Mass Spectrometry

(47) Preparative Reverse Phase HPLC Method:

(48) Compounds purified by mass directed preparative HPLC using ES+/ES− on a Waters FractionLynx Autopurification system comprising a 2767 injector/collector with a 2545 gradient pump, two 515 isocratic pumps, SFO, 2998 photodiode array (Wavelength range (nm): 210 to 400), 2424 ELSD and QDa mass spectrometer. A Waters Atlantis T3 5 micron 19×10 mm guard column was used with a Waters Atlantis T3 OBD, 5 micron 30×100 mm prep column.

(49) Ionisation method: Electrospray positive and negative: Cone (V) 20.00, Source Temperature (° C.) 120, Cone Gas Flow (L/Hr.) 50

(50) Mass range (Da): positive 100 to 800, negative 115 to 800.

(51) The preparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:

(52) TABLE-US-00010 Time Solvent Solvent Flow (mins) A (%) B (%) (ml/min) 0.00 100 0 35 2.00 100 0 35 2.01 100 0 35 7.0 90 10 35 7.3 0 100 35 9.2 0 100 35 9.8 99 1 35 11.35 99 1 35 11.40 99 1 35 515 pump 0 ml/min Acetonitrile (ACD) 515 pump 1 ml/min 90% Methanol/10% Water (make up pump) Solvent A: Water with 0.05% Trifluoroacetic Acid Solvent B: Acetonitrile with 0.05% Trifluoroacetic Acid

PREPARATION EXAMPLES

Example 1: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate A1

(53) ##STR00066##

Step 1: Preparation of tributyl(pyridazin-4-yl)stannane

(54) ##STR00067##

(55) To a solution of lithium diisopropylamide (1M solution in tetrahydrofuran, 125 mL) at −78° C. under nitrogen was added a solution of pyridazine (10 g) and tri-n-butyltin chloride (44.6 g) in THF (100 mL) drop wise. The reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was warmed to room temperature and quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was dried over sodium sulfate, concentrated and purified by chromatography on silica eluting with 30% ethyl acetate in hexanes to afford tributyl(pyridazin-4-yl)stannane as a pale brown liquid.

(56) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.17 (t, 1H) 9.02 (dd, 1H) 7.54 (dd, 1H) 1.57-1.49 (m, 6H) 1.37-1.29 (m, 6H) 1.19-1.13 (m, 6H) 0.92-0.86 (m, 9H).

Step 2: Preparation of 2-pyridazin-4-ylpyrimidine

(57) ##STR00068##

(58) A solution of 2-bromopyrimidine (2.50 g) and tributyl(pyridazin-4-yl)stannane (5.80 g) in tetrahydrofuran (25 mL) was degassed with argon for 20 min. Tetrakis (triphenylphosphine) palladium (0) (1.80 g) was added to the reaction mixture at room temperature and then irradiated in a microwave at 120° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (100 mL). The organic layer was concentrated and purified by chromatography on silica eluting with 80% ethyl acetate in hexanes to give 2-pyridazin-4-ylpyrimidine as a beige solid.

(59) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.17 (dd, 1H) 9.39 (dd, 1H) 8.92 (d, 2H) 8.43 (dd, 1H) 7.39 (t, 1H).

Step 3: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate A1

(60) A mixture of 2-pyridazin-4-ylpyrimidine (0.120 g) and sodium 2-bromoethanesulfonate (0.196 g) was stirred in water (2.3 mL) at 100° C. for 42 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate as a beige solid.

(61) .sup.1H NMR (400 MHz, D.sub.2O) 10.19 (d, 1H) 9.84 (d, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.27-5.18 (m, 2H) 3.71-3.63 (m, 2H).

Example 2: Preparation of 4-pyridazin-4-ylpyrimidine

(62) ##STR00069##

(63) A microwave vial was charged with tributyl(pyridazin-4-yl)stannane (0.387 g), 4-chloropyrimidine (0.100 g), palladium (0) tetrakis(triphenylphosphine) (0.101 g), cesium fluoride (0.265 g), cuprous iodide (0.00665 g) and 1,4-dioxane (4.37 mL) and heated to 140° C. under microwave conditions for 1 hour. The reaction mixture was concentrated and purified by chromatography on silica eluting with a gradient from 0 to 70% acetonitrile in dichloromethane to give 4-pyridazin-4-ylpyrimidine as an orange solid.

(64) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.90-9.83 (m, 1H) 9.41 (dd, 2H) 8.97 (d, 1H) 8.21-8.13 (m, 1H) 7.89 (dd, 1H).

Example 3: Preparation of methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide A2

(65) ##STR00070##

(66) Methyl bromoacetate (0.755 g) was added drop wise to a solution of 2-pyridazin-4-ylpyrimidine (0.505 g) in acetone (6.4 mL) and heated at 60° C. for 24 hours. The reaction mixture was concentrated and the residue triturated with dichloromethane. The resulting solid was filtered, washed with acetone and dried to give methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide as a brown solid.

(67) .sup.1H NMR (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.84 (d, 1H) 9.30 (dd, 1H) 9.01 (d, 2H) 7.66 (t, 1H) 5.84 (s, 2H) 3.79 (s, 3H).

Example 4: Preparation of (4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methanesulfonate A3

(68) ##STR00071##

(69) Methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide (0.420 g) was stirred in trimethylsilyl chlorosulfonate (4.96 g) at 80° C. for 66 hours. The reaction mixture was carefully quenched with water, concentrated and purified by preparative reverse phase HPLC to give (4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methanesulfonate as a pale brown solid.

(70) .sup.1H NMR (400 MHz, D.sub.2O) 10.26 (brs, 1H) 9.94 (brd, 1H) 9.27-9.39 (m, 1H) 8.96-9.14 (m, 2H) 7.56-7.73 (m, 1H) 5.97 (s, 2H).

Example 5: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A6

(71) ##STR00072##

(72) To a solution of 2-pyridazin-4-ylpyrimidine (0.200 g) in 1,4-dioxane (3.79 mL) was added 1,3-propanesultone (0.189 g). The mixture was stirred at 90° C. for 44 hours. The resulting solid was filtered off and washed with acetone. The solid was purified by preparative reverse phase HPLC to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate.

(73) .sup.1H NMR (400 MHz, D.sub.2O) 10.18 (d, 1H) 9.80 (d, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.01 (t, 2H) 2.98 (t, 2H) 2.53 (quin, 2H).

Example 6: Preparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate A9

(74) ##STR00073##

Step 1: Preparation of 2-pyridazin-4-ylpyrazine

(75) ##STR00074##

(76) A mixture of tributyl(pyridazin-4-yl)stannane (3.87 g), 2-chloropyrazine (1.00 g), palladium (0) tetrakis(triphenylphosphine) (1.03 g) and 1,4-dioxane (43.7 mL) was heated to 140° C. under microwave conditions for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 50% acetonitrile in dichloromethane to give 2-pyridazin-4-ylpyrazine as an off white solid.

(77) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.87 (dd, 1H) 9.39 (dd, 1H) 9.19 (d, 1H) 8.81-8.75 (m, 1H) 8.72 (d, 1H) 8.11 (dd, 1H).

Step 2: Preparation of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate Bromide

(78) ##STR00075##

(79) Methyl 3-bromopropanoate (0.518 mL) was added to a solution of 2-pyridazin-4-ylpyrazine (0.250 g) in acetonitrile (15.8 mL). The reaction mixture was heated to 80° C. for 24 hours. The reaction mixture was concentrated and the residue taken up in water and washed with dichloromethane. The aqueous phase was concentrated to give crude methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide (as a 1:1 mixture with 3-(5-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid bromide) as a brown gum, which was used crude in subsequent reactions.

Step 3: Preparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic Acid 2,2,2-trifluoroacetate A9

(80) The crude mixture of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide (0.515 g) and conc. hydrochloric acid (11.1 mL) was heated to 80° C. for 4 hours. The reaction mixture was cooled and allowed to stand overnight. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate as a brown gum.

(81) .sup.1H NMR (400 MHz, CD.sub.3OD) 10.28 (d, 1H) 10.00 (d, 1H) 9.62 (d, 1H) 9.28 (dd, 1H) 8.96-8.93 (m, 1H) 8.90 (d, 1H) 5.19-5.12 (t, 2H) 3.28 (t, 2H).

Example 7: Preparation of 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate A11

(82) ##STR00076##

Step 1: Preparation of 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate

(83) ##STR00077##

(84) Boc-hydrazide (1.00 g) was added to a solution of 2,2-dimethylpropyl ethenesulfonate (1.35 g) in methanol (10.1 mL) and heated to 70° C. for 24 hours. The reaction was concentrated to give 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate as a thick yellow liquid.

(85) .sup.1H NMR (400 MHz, CDCl.sub.3) 3.90 (s, 2H) 3.38-3.30 (m, 4H) 1.50-1.43 (s, 9H) 1.00-0.97 (s, 9H).

Step 2: Preparation of [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium Chloride

(86) ##STR00078##

(87) A mixture of 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate (1.00 g) and 3M methanolic hydrogen chloride (24.2 mL) was heated to 70° C. for 7 hours. The reaction mixture was concentrated to give [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride as a pink gum that solidified on standing.

(88) .sup.1H NMR (400 MHz, CD.sub.3OD) 3.95 (s, 2H) 3.59-3.53 (m, 2H) 3.44-3.39 (m, 2H) 1.00 (s, 9H) sample contained ˜20% methanol and was used as such.

Step 3: Preparation of 4-(3-furyl)pyridazine

(89) ##STR00079##

(90) To a mixture of 4-bromopyridazin-1-ium bromide (2.50 g), sodium carbonate (2.2 g), degassed toluene (17.3 mL) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride (0.634 g) was added a solution of 3-furylboronic acid (1.00 g) in ethanol (17.3 mL). The mixture was heated to 80° C. under nitrogen atmosphere for 24 hours. The reaction mixture was filtered through celite and concentrated. The residue was partitioned between water and dichloromethane then extracted with further dichloromethane. The combined organic layers were washed with brine and dried with magnesium sulfate. The concentrated filtrate was purified on silica eluting with a gradient of 0-100% ethyl acetate in iso-hexane to give 4-(3-furyl)pyridazine as a dark red semi-solid.

(91) .sup.1H NMR (400 MHz, CD.sub.3OD) 9.45 (s, 1H) 9.03-9.16 (m, 1H) 8.36 (s, 1H) 7.86 (dd, 1H) 7.71 (t, 1H) 7.04 (d, 1H).

Step 4: Preparation of 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine

(92) ##STR00080##

(93) A mixture of 4-(3-furyl)pyridazine (0.025 g) and sodium bicarbonate (0.14 g) in methanol (0.5 mL) was cooled to −10° C. and bromine (0.069 g) was added drop wise. After 30 minutes the reaction was quenched with 1:1 sat. aqueous sodium bicarbonate and 1M aqueous sodium thiosulfate (3 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was concentrated to give crude 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine.

(94) .sup.1H NMR (400 MHz, CD.sub.3OD) 9.42-9.41 (m, 1H) 9.20-9.19 (m, 1H) 7.85 (dt, 1H) 7.02-6.94 (m, 1H) 6.08-5.77 (m, 2H) 3.46 (d, 3H) 3.42 (d, 3H).

Step 5: Preparation of 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate A11

(95) A mixture of 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine (0.500 g) and [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride (0.658 g) was heated in aqueous 3M hydrochloric acid (12 mL) at 60° C. for 2 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate as a brown solid.

(96) .sup.1H NMR (400 MHz, D.sub.2O) 9.80-9.97 (m, 2H) 9.62-9.75 (m, 1H) 9.35-9.50 (m, 1H) 8.97 (dd, 1H) 8.19-8.42 (m, 1H) 5.20-5.29 (m 2H) 3.59-3.73 (m 2H).

Example 8: Preparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic Acid Chloride A29

(97) ##STR00081##

(98) A column packed with ion exchange resin (5.84 g, Discovery DSC-SCX) was washed with water (3 column volumes). The 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (0.292 g) dissolved in a minimum amount of water was loaded onto the column. The column was first eluted with water (3 column volumes) and then eluted with 2M hydrochloric acid (3 column volumes). The collected washings were concentrated to give 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride as a yellow solid.

(99) .sup.1H NMR (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.80 (d, 1H) 9.35 (d, 1H) 9.05 (dd, 1H) 8.87-8.82 (m, 1H) 8.76 (d, 1H) 5.08 (t, 2H) 3.22 (t, 2H).

Example 9: Preparation of Methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate Chloride A30

(100) ##STR00082##

(101) A column packed with ion exchange resin (1.6 g, Discovery DSC-SCX) was washed with methanol (3 column volumes). The 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (0.081 g) dissolved in a minimum amount of methanol was loaded onto the column. The column was first eluted with methanol (3 column volumes) and then eluted with 3M methanolic hydrochloric acid (3 column volumes). The collected washings were concentrated to give methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate chloride as a blue gum.

(102) .sup.1H NMR (400 MHz, CD.sub.3OD) 10.30-10.26 (m, 1H) 10.04-10.00 (m, 1H) 9.66-9.64 (m, 1H) 9.33-9.30 (m, 1H) 8.97-8.93 (m, 1H) 8.91-8.88 (m, 1H) 5.25-5.14 (m, 2H) 3.71-3.68 (m, 3H) 3.35-3.27 (m, 2H).

Example 10: Preparation of Isopropyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate A81

(103) ##STR00083##

(104) Sodium iodide (0.24 g) and isopropyl 3-chloropropanoate (0.357 g) were added to a solution of 2-pyridazin-4-ylpyrimidine (0.25 g) in acetonitrile (6 mL) and heated at 80° C. for 25 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give isopropyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate as a brown gum.

(105) .sup.1H NMR (400 MHz, CD.sub.3OD) 10.29-10.43 (m, 1H) 10.02 (d, 1H) 9.36-9.49 (m, 1H) 9.04-9.18 (m, 2H) 7.63-7.76 (m, 1H) 5.10-5.24 (m, 2H) 4.92-5.04 (m, 1H) 3.14-3.41 (m, 2H) 1.12-1.25 (m, 6H).

Example 11: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic Acid Bromide A107

(106) ##STR00084##

(107) A mixture of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate (0.2 g), concentrated hydrogen bromide (1 mL, 48 mass %) and water (5 mL) was heated to 80° C. for 4 hours and left to cool overnight. After a further 4 hours heating at 80° C. the reaction mixture was concentrated and the resulting yellow gum was triturated with acetone to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid bromide as a cream solid.

(108) .sup.1H NMR (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.86 (d, 1H) 9.21-9.15 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H).

Example 12: Preparation of 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A134

(109) ##STR00085##

Step 1: Preparation of Methyl 2-(2,2-dimethylpropoxysulfonyl)acetate

(110) ##STR00086##

(111) Methyl 2-chlorosulfonylacetate (0.5 g) was added drop wise to a cooled (ice bath) solution of 2,2-dimethylpropan-1-ol (0.306 g) and pyridine (0.284 mL) in dichloromethane (14.5 mL). The reaction mixture was stirred cold for a further 2 hours then partitioned with aqueous sat. ammonium chloride. The aqueous phase was extracted with further dichloromethane (×2). The combined organic extracts were concentrated and passed through a plug of silica eluting with diethyl ether. The filtrate was concentrated to give methyl 2-(2,2-dimethylpropoxysulfonyl)acetate as a yellow liquid.

(112) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.11 (s, 2H) 4.00 (s, 2H) 3.84 (s, 3H) 1.01 (s, 9H).

Step 2: Preparation of Methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate

(113) ##STR00087##

(114) A mixture of sodium hydride (60% in mineral oil, 0.039 g) in tetrahydrofuran (4.46 mL) was cooled (ice bath) to 0° C. under nitrogen atmosphere. To this was added a solution of methyl 2-(2,2-dimethylpropoxysulfonyl)acetate (0.2 g) in tetrahydrofuran (1.78 mL) and stirred at this temperature for 5 minutes. Iodomethane (0.067 mL) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was partitioned between 2M hydrochloric acid and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (×2). The combined organic extracts were dried with magnesium sulfate and concentrated to give methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate as a yellow liquid.

(115) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.12-4.09 (m, 1H) 3.97 (d, 2H) 3.83 (s, 3H) 1.69 (d, 3H) 0.99 (s, 9H).

Step 3: Preparation of 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate

(116) ##STR00088##

(117) To a cooled (ice bath) solution of methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate (1 g) in dichloromethane (126 mL) was added dropwise, under nitrogen atmosphere, diisobutylaluminum hydride (1M in dichloromethane, 10.5 mL) maintaining the temperature below 5° C. during the addition. The reaction mixture was stirred at 0° C. for 1 hour. Propan-2-ol (12.6 mL) was added and the reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. The reaction mixture was partitioned between 2M aqueous hydrochloric acid and dichloromethane. The organic phase was dried with magnesium sulfate, concentrated and chromatographed on silica using a gradient from 0 to 100% EtOAc in isohexane to give 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate as a colourless liquid.

(118) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.03-3.84 (m, 4H) 3.43-3.33 (m, 1H) 2.60-2.52 (m, 1H) 1.45 (d, 3H) 1.00 (s, 9H).

Step 4: Preparation of 1-hydroxypropane-2-sulfonic Acid

(119) ##STR00089##

(120) A mixture of 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate (0.25 g) and 6M aqueous hydrochloric acid (9.51 mL) was heated to 95° C. for 4 hours. The reaction mixture was cooled and concentrated by freeze drying.

(121) .sup.1H NMR (400 MHz, D.sub.2O) 3.88-3.78 (m, 1H) 3.56-3.47 (m, 1H) 2.98-2.89 (m, 1H) 1.18 (d, 3H).

Step 5: Preparation of 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A134

(122) To a cooled (ice bath) solution of 2-pyridazin-4-ylpyrimidine (0.1 g) in dry acetonitrile (6.32 mL) was added 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (0.131 mL) and the reaction mixture was stirred at room temperature for 15 minutes. To this mixture was added triphenylphosphine (0.332 g) and a solution of 1-hydroxypropane-2-sulfonic acid (0.133 g) in acetonitrile (0.5 mL), followed by drop wise addition of diisopropyl azodicarboxylate (0.25 mL). The reaction mixture was heated at 80° C. for 170 hours. The reaction mixture was concentrated and partitioned between water and diethyl ether. The aqueous layer was concentrated and purified by preparative reverse phase HPLC to give 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate as a white solid.

(123) .sup.1H NMR (400 MHz, D.sub.2O) 10.20-10.18 (m, 1H) 9.81 (dd, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.65 (t, 1H) 5.10-5.07 (m, 2H) 3.84-3.74 (m, 1H) 1.39 (d, 3H).

Example 13: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate A40

(124) ##STR00090##

(125) To a mixture of 2-pyridazin-4-ylpyrimidine (0.5 g) in water (10 mL) was added but-2-enoic acid (0.816 g). The mixture was heated at reflux for 40 hours. The reaction mixture was concentrated and the resulting solid was triturated with tert-butylmethylether and acetone. The solid was purified by preparative reverse phase HPLC to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate.

(126) .sup.1H NMR (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.92 (d, 1H) 9.18-9.26 (m, 1H) 8.99-9.05 (m, 2H) 7.68 (t, 1H) 5.49-5.60 (m, 1H) 3.39 (dd, 1H) 3.10-3.21 (m, 1H) 1.71 (d, 3H).

Example 14: Preparation of 2-(3-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate

(127) ##STR00091##

Step 1: Preparation of tributyl-(3-chloro-6-methoxy-pyridazin-4-yl)stannane

(128) ##STR00092##

(129) A solution of lithium diisopropylamide (1M in tetrahydrofuran, 1.7 mL) was cooled to −78° C. To this was added a solution of 3-chloro-6-methoxy-pyridazine (0.2 g) in tetrahydrofuran (2 mL) whilst maintaining the temperature below −70° C. The resulting mixture was stirred at −78° C. for 40 minutes. To this was slowly added tri-n-butyltin chloride (0.47 mL) at −78° C. over a period of 10 minutes, then stirring was continued at −78° C. for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (50 mL). The aqueous layer was extracted with further ethyl acetate (50 mL). The combined organic layers were dried over sodium sulphate, concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give crude tributyl-(3-chloro-6-methoxy-pyridazin-4-yl)stannane (HPLC retention time 2.07 min) in a 2:1 ratio with the isomer tributyl-(6-chloro-3-methoxy-pyridazin-4-yl)stannane (HPLC retention time 1.79 min).

Step 2: Preparation of 3-chloro-6-methoxy-4-pyrimidin-2-yl-pyridazine

(130) ##STR00093##

(131) A solution of the crude tributyl-(3-chloro-6-methoxy-pyridazin-4-yl)stannane (15.2 g) in 1,4-dioxane (304 mL) was degassed with nitrogen for 20 minutes. To this was added cuprous iodide (1.02 g), tris(dibenzylideneacetone)dipalladium(0) (1.65 g) and triphenylphosphine (0.763 g) and again degassed for 20 minutes. After the addition of 2-bromopyrimidine (6.13 g) the reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled, concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give a mixture of isomers 3-chloro-6-methoxy-4-pyrimidin-2-yl-pyridazine and 6-chloro-3-methoxy-4-pyrimidin-2-yl-pyridazine, as an off-white solid, which was used crude in the next step.

Step 3: Preparation of 6-methoxy-3-methyl-4-pyrimidin-2-yl-pyridazine

(132) ##STR00094##

(133) To a solution of crude 3-chloro-6-methoxy-4-pyrimidin-2-yl-pyridazine (1.5 g) in 1,4-dioxane (45 mL), under a nitrogen atmosphere, was added methylboronic acid (1.2 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.49 g). The mixture was degassed with nitrogen for 15 minutes then heated to 100° C. Cesium carbonate (4.4 g) was added over 5 minutes and the mixture heated at 100° C. for 3 hours. The reaction mixture was cooled, concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give 6-methoxy-3-methyl-4-pyrimidin-2-yl-pyridazine.

(134) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.91 (d, 1H) 8.82-8.99 (m, 1H) 7.52 (s, 1H) 7.37 (t, 1H) 4.17 (s, 3H) 2.88 (s, 3H).

Step 4: Preparation of 6-methyl-5-pyrimidin-2-yl-pyridazin-3-ol

(135) ##STR00095##

(136) A mixture of 6-methoxy-3-methyl-4-pyrimidin-2-yl-pyridazine (0.5 g) in concentrated hydrogen bromide (10 mL, 48 mass %) was heated at 80° C. for 16 hours. The reaction mixture was cooled, concentrated and azeotroped with toluene (2×30 mL) to give crude 6-methyl-5-pyrimidin-2-yl-pyridazin-3-ol which was used in the next step without further purification.

Step 5: Preparation of 6-chloro-3-methyl-4-pyrimidin-2-yl-pyridazine

(137) ##STR00096##

(138) A mixture of 6-methyl-5-pyrimidin-2-yl-pyridazin-3-ol (0.025 g) in phosphorus oxychloride (0.25 mL) was heated at 80° C. for 3 hours. The reaction mixture was concentrated and the residue was diluted with ice cold water (2 mL) and neutralised with sodium bicarbonate solution. The aqueous was extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulphate and concentrated to give 6-chloro-3-methyl-4-pyrimidin-2-yl-pyridazine, which was used in the next step without further purification.

(139) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.94 (d, 2H) 8.13 (s, 1H) 7.41 (t, 1H) 3.03 (s, 3H).

Step 6: Preparation of 3-methyl-4-pyrimidin-2-yl-pyridazine

(140) ##STR00097##

(141) To a solution of 6-chloro-3-methyl-4-pyrimidin-2-yl-pyridazine (0.37 g) in ethanol (15 mL) was added triethylamine (0.24 g) and 10% palladium on carbon (0.035 g). The mixture was hydrogenated under balloon pressure for 1 hour. The reaction mixture was diluted with ethanol (10 mL) and filtered through celite, washing through with further ethanol (2×20 mL). The filtrate was concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give 3-methyl-4-pyrimidin-2-yl-pyridazine as a white solid.

(142) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.25 (d, 1H) 8.93 (d, 2H) 8.02 (d, 1H) 7.38 (t, 1H) 3.04 (s, 3H).

Step 7: Preparation of 2-(3-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate A88

(143) A mixture of 3-methyl-4-pyrimidin-2-yl-pyridazine (0.125 g) and sodium 2-bromoethanesulfonate (0.153 g) in water (2.5 mL) was heated at reflux for 18 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 2-(3-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate, A88.

(144) .sup.1H NMR (400 MHz, D.sub.2O) 9.76 (d, 1H) 9.69-9.88 (m, 1H) 9.02 (d, 1H) 8.77 (d, 1H) 7.69 (t, 1H) 5.21 (t, 2H) 3.71 (t, 2H) 2.94 (s, 3H).

Example 15: Preparation of 3-bromo-N-methylsulfonyl-propanamide

(145) ##STR00098##

(146) To a solution of methanesulfonamide (0.5 g) in toluene (25.8 mL) was added 3-bromopropionyl chloride (1.77 g) drop wise at room temperature. The reaction mixture was heated at 110° C. for 4 hours. The reaction was cooled in ice and the resulting solid was filtered and washed with cold toluene to give 3-bromo-N-methylsulfonyl-propanamide as a colourless solid.

(147) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.28 (br s, 1H) 3.62 (t, 2H) 3.34 (s, 3H) 2.94 (t, 2H).

Example 16: Preparation of 2-hydroxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A143

(148) ##STR00099##

(149) A mixture of 2-pyridazin-4-ylpyrimidine (0.3 g), water (6 mL) and sodium 3-chloro-2-hydroxy-propane-1-sulfonate (0.45 g) was heated at reflux for 3 days. The reaction mixture was concentrated and the resulting solid was washed with t-butylmethyl ether and acetone. The solid was purified by preparative reverse phase HPLC to give 2-hydroxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate, A143.

(150) .sup.1H NMR (400 MHz, D.sub.2O) 10.24 (d, 1H) 9.80 (d, 1H) 9.25 (dd, 1H) 9.04 (d, 2H) 7.68 (t, 1H) 5.21 (dd, 1H) 4.93 (dd, 1H) 4.64-4.71 (m, 1H) 3.19-3.36 (m 2H).

Example 17: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic Acid 2,2,2-trifluoroacetate A125

(151) ##STR00100##

(152) 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride (0.119 g) was stirred in 2,2,2-trifluoroacetic acid (4 mL) at room temperature for two hours. The reaction mixture was concentrated and freeze dried to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate, A125, as a pale yellow gum, which solidified on standing.

(153) .sup.1H NMR (400 MHz, D.sub.2O) 10.18-10.13 (m, 1H) 9.87-9.82 (m, 1H) 9.20-9.14 (m, 1H) 8.98 (d, 2H) 7.63 (s, 1H) 5.10 (s, 2H) 3.24 (t, 2H).

Example 18: Preparation of 3-methyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic Acid 2,2,2-trifluoroacetate A131

(154) ##STR00101##

(155) A mixture of 2-pyridazin-4-ylpyrimidine (1 g), 3,3-dimethylacrylic acid (1.96 g), 2,2,2-trifluoroacetic acid (5 mL) and water (5 mL) was heated at 100° C. under microwave conditions for 18 hours. The reaction mixture was concentrated and the resulting solid was washed with diethyl ether (5×10 mL). The solid was purified by preparative reverse phase HPLC to give 3-methyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate, A131.

(156) .sup.1H NMR (400 MHz, D.sub.2O) 10.18 (m, 1H) 9.97 (m, 1H) 9.21 (m, 1H) 8.98 (m, 2H) 7.61 (m, 1H) 3.36 (s, 2H) 1.94 (s, 6H).

Example 19: Preparation of 5-methylsulfonyl-2-pyridazin-4-yl-pyrimidine

(157) ##STR00102##

Step 1: Preparation of 5-chloro-2-pyridazin-4-yl-pyrimidine

(158) ##STR00103##

(159) A solution of 2,5-dichloropyrimidine (6 g) in 1,4-dioxane (60 mL) was degassed with nitrogen for 20 minutes. To this was added tributyl(pyridazin-4-yl)stannane (14.87 g), tetrakis(triphenylphosphine)palladium(0) (4.66 g) and the mixture heated at 110° C. for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×100 mL). The organic layers were concentrated and chromatographed on silica eluting with 75% ethyl acetate in hexanes to give 5-chloro-2-pyridazin-4-yl-pyrimidine as a pinkish solid.

(160) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.12 (dd, 1H) 9.38 (dd, 1H) 8.86 (s, 2H) 8.38 (dd, 1H)

Step 2: Preparation of 5-methylsulfonyl-2-pyridazin-4-yl-pyrimidine

(161) To a solution of 5-chloro-2-pyridazin-4-yl-pyrimidine (0.8 g) in N,N-dimethylformamide (8 mL) was added sodium methanesulfinate (1 g) and the mixture heated at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and poured into ice cold water (50 mL). The resulting solid was filtered and dried to give 5-methylsulfonyl-2-pyridazin-4-yl-pyrimidine as a white solid.

(162) .sup.1H NMR (400 MHz, de-DMSO) 10.01-10.10 (m, 1H) 9.45-9.60 (m, 3H) 8.46-8.55 (m, 1H), 3.48 (s, 3H).

Example 20: Preparation of N,N-dimethyl-2-pyridazin-4-yl-pyrimidin-5-amine

(163) ##STR00104##

(164) To a mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (0.035 g) in dimethylamine (40 mass % in water, 1 mL) in a microwave vial was added N,N-diisopropylethylamine (0.16 mL). The mixture was heated under microwave conditions at 150° C. for 6 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (15 mL). The aqueous layer was extracted with further ethyl acetate (30 mL). The organic layers were dried over sodium sulfate and concentrated to give N,N-dimethyl-2-pyridazin-4-yl-pyrimidin-5-amine as a yellow solid.

(165) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.05 (s, 1H) 9.24 (d, 1H) 8.30 (s, 2H) 8.25 (dd, 1H) 3.12 (s, 6H).

Example 21: Preparation of 2-pyridazin-4-ylpyrimidine-5-carbonitrile

(166) ##STR00105##

(167) A mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (2 g), zinc cyanide (0.75 g), zinc (0.068 g), tris(dibenzylideneacetone)dipalladium(0) (0.98 g) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.99 g) in N,N-dimethylacetamide (16 mL) was heated at 120° C. under nitrogen atmosphere for 12 hours. After cooling, the reaction was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give 2-pyridazin-4-ylpyrimidine-5-carbonitrile as a yellow solid.

(168) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.19-10.20 (m, 1H) 9.50 (d, 1H) 9.19 (s, 2H) 8.47-8.49 (m, 1H).

Example 22: Preparation of 5-cyclopropyl-2-pyridazin-4-yl-pyrimidine

(169) ##STR00106##

(170) A mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (0.05 g), tricyclohexylphosphane (0.007 g), cyclopropylboronic acid (0.045 g), tris(dibenzylideneacetone)dipalladium(0) (0.024 g) and potassium phosphate (0.07 g) in dioxane (0.5 mL) was heated at 120° C. under nitrogen atmosphere for 4 hours. The reaction was concentrated and chromatographed on silica eluting with 60% ethyl acetate in cyclohexane to give 5-cyclopropyl-2-pyridazin-4-yl-pyrimidine as a yellow solid.

(171) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.00-10.21 (m, 1H) 9.27-9.40 (m, 1H) 8.54-8.67 (m, 2H) 8.35-8.46 (m, 1H) 2.14-2.22 (m, 1H) 1.18-1.24 (m, 2H) 0.87-0.93 (m, 2H).

Example 23: Preparation of 1-(2-pyridazin-4-ylpyrimidin-5-yl)ethanone

(172) ##STR00107##

Step 1: Preparation of 5-(1-ethoxyvinyl)-2-pyridazin-4-yl-pyrimidine

(173) ##STR00108##

(174) A mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (1 g), tributyl(1-ethoxyvinyl)stannane (2.062 g), palladium(II)bis(triphenylphosphine) dichloride (0.368 g) in N,N-dimethylformamide (10 mL) was heated at 70° C. for 16 hours. After cooling the reaction was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give 5-(1-ethoxyvinyl)-2-pyridazin-4-yl-pyrimidine as a yellow solid.

(175) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.17 (s, 1H) 9.36-9.47 (m, 1H) 9.09 (s, 2H) 8.87 (s, 1H) 4.83-4.88 (m, 1H) 4.46-4.49 (m, 1H) 3.97-4.04 (m, 2H) 1.45-1.51 (m, 3H).

Step 2: Preparation of 1-(2-pyridazin-4-ylpyrimidin-5-yl)ethanone

(176) A solution of 5-(1-ethoxyvinyl)-2-pyridazin-4-yl-pyrimidine (0.4 g), acetone (4 mL) and 2M aqueous hydrochloric acid (0.88 mL) was heated at 65° C. for 18 hours. After cooling the reaction was partitioned between water and ethyl acetate. The organic layer was washed further with water and brine. The organic layer was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give 1-(2-pyridazin-4-ylpyrimidin-5-yl)ethanone.

(177) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.15 (s, 1H) 9.41 (d, 1H) 8.88 (s, 2H) 8.42-8.44 (m, 1H) 2.10 (s, 3H).

Example 24: Preparation of N,N-dimethyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide

(178) ##STR00109##

Step 1: Preparation of methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate

(179) ##STR00110##

(180) To a solution of 2-pyridazin-4-ylpyrimidine-5-carbonitrile (0.52 g) in methanol (5.2 mL) was added a solution of potassium hydroxide (0.023 g) in water (5.2 mL) at 0° C. After stirring at 0° C. for 90 minutes the reaction mixture was acidified with acetic acid to pH 3. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate as a brown solid.

(181) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.22 (s, 1H) 9.41-9.46 (m, 3H) 8.50 (dd, 1H) 4.05 (s, 3H).

Step 2: Preparation of N,N-dimethyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide

(182) A mixture of methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate (0.02 g) and N-methylmethanamine (2 mL) in a sealed vial was heated at 85° C. for 2 hours. The reaction mixture was concentrated to give N,N-dimethyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide as a white solid.

(183) .sup.1H NMR (400 MHz, D.sub.2O) 9.82-9.88 (m, 1H) 9.28-9.32 (m, 1H) 8.98 (s, 2H) 8.42-8.44 (m, 1H) 2.98-3.02 (m, 6H).

Example 25: Preparation of N-methyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide

(184) ##STR00111##

(185) A mixture of methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate (0.02 g) and methylamine in methanol (2M solution, 0.2 mL) in a sealed vial was heated at 100° C. for 2 hours. The reaction mixture was concentrated to give N-methyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide as a brown solid.

(186) .sup.1H NMR (400 MHz, CD.sub.3OD) 10.05-10.20 (m, 1H) 9.40-9.45 (m, 1H) 9.27-9.39 (m, 2H) 8.66 (dd, 1H) 2.99 (s, 3H).

Example 26: Preparation of (2-pyridazin-4-ylpyrimidin-4-yl)methanol

(187) ##STR00112##

Step 1: Preparation of 2-pyridazin-4-ylpyrimidine-4-carbonitrile

(188) ##STR00113##

(189) A solution of 2-chloropyrimidine-4-carbonitrile (4.89 g) in tetrahydrofuran (50 mL) was degassed with nitrogen for 30 minutes. To this was added tributyl(pyridazin-4-yl)stannane (12.9 g) and tetrakis(triphenylphosphine)palladium(0) (4.06 g) and the reaction mixture was heated at 110° C. for 12 hours. After cooling the reaction was partitioned between water and ethyl acetate and extracted with further ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give 2-pyridazin-4-ylpyrimidine-4-carbonitrile as a brown solid.

(190) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.17 (dd, 1H) 9.46 (dd, 1H) 9.09-9.20 (m, 1H) 8.36-8.53 (m, 1H) 7.72 (d, 1H).

Step 2: Preparation of Methyl 2-pyridazin-4-ylpyrimidine-4-carboxylate

(191) ##STR00114##

(192) To a solution of 2-pyridazin-4-ylpyrimidine-4-carbonitrile (2.7 g) in methanol (27 mL) was added a solution of potassium hydroxide (0.55 g) in water (27 mL) at 0° C. After stirring at 0° C. for 90 minutes the reaction mixture was acidified with acetic acid to pH 3. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 2-pyridazin-4-ylpyrimidine-4-carboxylate as a brown solid.

(193) .sup.1H NMR (400 MHz, CDCl.sub.3) 10.24 (s, 1H) 9.44 (dd, 1H) 9.17 (d, 1H) 8.53 (dd, 1H) 8.06 (d, 1H) 4.11 (s, 3H).

Step 3: Preparation of (2-pyridazin-4-ylpyrimidin-4-yl)methanol

(194) To a solution of methyl 2-pyridazin-4-ylpyrimidine-4-carboxylate (0.05 g) in methanol (0.5 mL) under a nitrogen atmosphere was added sodium borohydride (0.018 g) slowly, keeping the reaction temperature below 20° C. The mixture was stirred for 16 hours at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate (3×30 mL). The aqueous layer was further extracted with 10% isopropanol in chloroform (100 mL). The combined organic layers were dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give (2-pyridazin-4-ylpyrimidin-4-yl)methanol as a yellow solid.

(195) .sup.1H NMR (400 MHz, de-DMSO) 10.00 (s, 1H) 9.45 (d, 1H) 9.02 (d, 1H) 8.40-8.44 (m, 1H) 7.68 (d, 1H) 4.70 (d, 2H).

Example 27: Preparation of 2-methyl-1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A114

(196) ##STR00115##

Step 1: Preparation of Methyl 2-(2,2-dimethylpropoxysulfonyl)-2-methyl-propanoate

(197) ##STR00116##

(198) To sodium hydride (60% in mineral oil, 0.392 g), under a nitrogen atmosphere and cooled in an ice bath, was added tetrahydrofuran (22.3 mL) followed by a solution of methyl 2-(2,2-dimethylpropoxysulfonyl)acetate (1 g) in tetrahydrofuran (8.92 mL). The reaction mixture was stirred at this temperature for 5 minutes and then iodomethane (0.694 mL) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 2-(2,2-dimethylpropoxysulfonyl)-2-methyl-propanoate as a yellow liquid.

(199) .sup.1H NMR (400 MHz, CDCl.sub.3) 3.95 (s, 2H) 3.82 (s, 3H) 1.71 (s, 6H) 0.98 (s, 9H).

Step 2: Preparation of 2,2-dimethylpropyl 1-hydroxy-2-methyl-propane-2-sulfonate

(200) ##STR00117##

(201) Diisobutylaluminum hydride (1M in dichloromethane, 6.62 mL) was added drop wise to a cooled (ice bath) solution of methyl 2-(2,2-dimethylpropoxysulfonyl)-2-methyl-propanoate (0.668 g) in dichloromethane (79.4 mL) under a nitrogen atmosphere, maintaining the temperature below 5° C. during the addition. The reaction mixture was stirred at 0° C. for 1 hour. Propan-2-ol (7.94 mL) was added to the reaction mixture and stirring continued at 0° C. for a further hour, then it was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane and washed with 2M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 0-100% ethyl acetate in hexanes to give 2,2-dimethylpropyl 1-hydroxy-2-methyl-propane-2-sulfonate as a clear colourless liquid.

(202) .sup.1H NMR (400 MHz, CDCl.sub.3) 3.94 (s, 2H) 3.80 (d, 2H) 2.53 (t, 1H) 1.46 (s, 6H) 1.00 (s, 9H).

Step 3: Preparation of 1-hydroxy-2-methyl-propane-2-sulfonic Acid

(203) ##STR00118##

(204) A mixture of 2,2-dimethylpropyl 1-hydroxy-2-methyl-propane-2-sulfonate (0.393 g) and 6M aqueous hydrochloric acid (14.0 mL) was heated to 95° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was taken up in acetonitrile, dried over magnesium sulfate and concentrated to give 1-hydroxy-2-methyl-propane-2-sulfonic acid as a colourless gum.

(205) .sup.1H NMR (400 MHz, D.sub.2O) 3.93-3.86 (m, 2H) 1.15-1.08 (m, 6H).

Step 4: Preparation of 2-methyl-1-(trifluoromethylsulfonyloxy)propane-2-sulfonate

(206) ##STR00119##

(207) A mixture of 2,6-dimethylpyridine (0.278 g) and 1-hydroxy-2-methyl-propane-2-sulfonic acid (0.200 g) in dichloromethane (2.33 mL) was cooled to 0° C. in an ice bath. Trifluoromethylsulfonyl trifluoromethanesulfonate (0.403 g) was added dropwise and the reaction mixture was stirred cold for 15 minutes then allowed to warm to room temperature. The reaction mixture was quenched with water and extracted with dichloromethane (×3). The combined organic extracts were dried over magnesium sulfate and concentrated to give 2-methyl-1-(trifluoromethylsulfonyloxy)propane-2-sulfonate as a brown gum.

(208) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.09 (s, 2H) 1.77 (s, 6H).

Step 5: Preparation of 2-methyl-1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A114

(209) A mixture of 2-pyridazin-4-ylpyrimidine (0.040 g), 2-methyl-1-(trifluoromethylsulfonyloxy)propane-2-sulfonate (0.072 g) and 1,4-dioxane (2.0 mL) was heated to 90° C. overnight. The reaction mixture was cooled, concentrated and purified by preparative reverse phase HPLC to give 2-methyl-1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A114 as a white solid.

(210) .sup.1H NMR (400 MHz, D.sub.2O) 10.17-10.12 (m, 1H) 9.75-9.71 (m, 1H) 9.15 (dd, 1H) 8.97 (d, 2H) 7.61 (t, 1H) 5.04 (s, 2H) 1.37 (s, 6H).

Example 28: Preparation of ethoxy-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]phosphinate A113

(211) ##STR00120##

Step 1: Preparation of 1-(2-diethoxyphosphorylethyl)-4-pyrimidin-2-yl-pyridazin-1-ium A124

(212) ##STR00121##

(213) To a mixture of 2-pyridazin-4-ylpyrimidine (0.5 g) in acetonitrile (10 mL) was added 1-bromo-2-diethoxyphosphoryl-ethane (0.929 g). The mixture was heated at reflux for 24 hours. The reaction was concentrated and the residue washed with ethyl acetate and acetone. The residue was purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to give 1-(2-diethoxyphosphorylethyl)-4-pyrimidin-2-yl-pyridazin-1-ium, A124.

(214) .sup.1H NMR (400 MHz, D.sub.2O) 10.26 (d, 1H) 9.89 (d, 1H) 9.27 (dd, 1H) 9.00-9.06 (m, 2H) 7.69 (t, 1H) 5.11-5.23 (m, 2H) 4.03-4.15 (m, 4H) 2.84 (dt, 2H) 1.21 (t, 6H).

Step 2: Preparation of ethoxy-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]phosphinate A113

(215) A mixture of 1-(2-diethoxyphosphorylethyl)-4-pyrimidin-2-yl-pyridazin-1-ium (0.2 g) in 2M aqueous hydrochloric acid (4 mL) was heated at 60° C. for 4 hours. The reaction was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give ethoxy-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]phosphinate, A113.

(216) .sup.1H NMR (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.86 (d, 1H) 9.23 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 5.06 (dt, 2H) 3.85 (quin, 2H) 2.44-2.53 (m 2H) 1.13 (t, 3H).

Example 29: Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic Acid Chloride A138

(217) ##STR00122##

Step 1: Preparation of 3-pyridazin-4-ylpyridazine

(218) ##STR00123##

(219) A microwave vial, under nitrogen atmosphere, was charged with tributyl(pyridazin-4-yl)stannane (0.697 g), 3-bromopyridazine (0.25 g), palladium (0) tetrakis(triphenylphosphine) (0.185 g) and 1,4-dioxane (7.86 mL) and heated at 14000 in the microwave for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 50% acetonitrile in dichloromethane to give 3-pyridazin-4-ylpyridazine as an orange solid.

(220) 1 HNMR (400 MHz, CDCl.sub.3) 9.94-9.89 (m, 1H) 9.42 (dd, 1H) 9.35 (dd, 1H) 8.24 (dd, 1H) 8.09 (dd, 1H) 7.79-7.72 (m, 1H).

Step 2: Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic Acid 2,2,2-trifluoroacetate A182

(221) ##STR00124##

(222) A mixture of 3-pyridazin-4-ylpyridazine (0.25 g), water (15 mL) and 3-bromopropanoic acid (0.363 g) was heated at 100° C. for 25 hours. The mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate, A182.

(223) 1H NMR (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.32 (dd, 1H) 9.10 (dd, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.13 (t, 2H) 3.26 (t, 2H) (one C.sub.02H proton missing).

Step 3: Preparation of 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic Acid Dichloride A234

(224) ##STR00125##

(225) A mixture of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (6.56 g) and 2M aqueous hydrochloric acid (114 mL) was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was taken up in a small amount of water and freeze dried. The resulting glassy yellow solid was stirred in acetone (105 mL) overnight. The solid material was collected by filtration, washed with further acetone and dried under vacuum to give 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic acid dichloride, A234, as a beige solid.

(226) 1H NMR (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.36 (br d, 1H) 9.10 (dd, 1H) 8.48-8.56 (m, 1H) 7.92-8.07 (m, 1H) 4.98-5.20 (m, 2H) 3.18-3.32 (m, 2H) (one CO.sub.2H proton missing)

Step 4: Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic Acid Chloride A138

(227) ##STR00126##

(228) A mixture of 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic acid dichloride (0.541 g) and 2-propanol (10 mL) was heated at 90° C. Water was added drop wise until a clear solution was obtained, this took ˜0.8 mL. To this was added further hot 2-propanol (10 mL) and the solution left to cool. Filtered off the precipitate and washed with cold 2-propanol and acetone and dried under vacuum to give 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride, A138, as a beige solid.

(229) 1H NMR (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.87 (d, 1H) 9.32 (dd, 1H) 9.12-9.08 (m, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.12 (t, 2H) 3.24 (t, 2H) (one C.sub.02H proton missing)

Example 30: Preparation of 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate Chloride A213

(230) ##STR00127##

Step 1: Preparation of 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate A5

(231) ##STR00128##

(232) A mixture of 3-pyridazin-4-ylpyridazine (0.41 g), sodium 2-bromoethanesulfonic acid (0.656 g) and water (7.78 mL) was heated at 100° C. for 17 hours. The reaction mixture was cooled, filtered through a syringe filter and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate as a yellow solid.

(233) 1H NMR (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.87 (d, 1H) 9.33 (dd, 1H) 9.12 (dd, 1H) 8.52 (dd, 1H) 7.99 (dd, 1H) 5.32-5.19 (m, 2H) 3.73-3.65 (m, 2H)

Step 2: Preparation of 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate Chloride A213

(234) A solution of 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate (0.2 g) and 2M aqueous hydrochloric acid (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was taken up in a small amount of water and freeze dried to give 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride as a cream glass like solid.

(235) 1H NMR (400 MHz, D.sub.2O) 10.13 (d, 1H) 9.86 (d, 1H) 9.35 (dd, 1H) 9.11 (dd, 1H) 8.57 (dd, 1H) 8.05 (dd, 1H) 5.27-5.21 (m, 2H) 3.71-3.64 (m, 2H) (one NH proton missing)

Example 31: Preparation of 4-pyridazin-4-ylpyrimidin-2-amine

(236) ##STR00129##

(237) A microwave vial, under nitrogen atmosphere, was charged with tributyl(pyridazin-4-yl)stannane (3.42 g), 4-pyridazin-4-ylpyrimidin-2-amine (0.727 g), palladium (0) tetrakis(triphenylphosphine) (0.892 g), N,N-diisopropylethylamine (1.35 mL) and 1,4-dioxane (38.6 mL) and heated to 140° C. in the microwave for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 70% acetonitrile in dichloromethane to give 4-pyridazin-4-ylpyrimidin-2-amine as a beige solid.

(238) 1H NMR (400 MHz, d.sub.6-DMSO) 9.82 (dd, 1H) 9.41 (dd, 1H) 8.47 (d, 1H) 8.22 (dd, 1H) 7.38 (d, 1H) 6.98 (br s, 2H)

Example 32: Preparation of 2-pyridazin-4-ylpyrimidin-4-ol

(239) ##STR00130##

(240) To a mixture of 2-pyridazin-4-ylpyrimidin-4-amine (0.1 g) and acetic acid (1 mL) was added a solution of sodium nitrite (0.12 g) in water (1 mL) drop wise at room temperature. The mixture was heated to 90° C. for 30 minutes. The reaction mixture was concentrated and the resulting solid washed with water and t-butylmethylether to give 2-pyridazin-4-ylpyrimidin-4-ol.

(241) 1H NMR (400 MHz, d.sub.6-DMSO) 12.39-13.52 (m, 1H) 9.82-9.86 (m, 1H) 9.46 (d, 1H) 8.37 (d, 1H) 8.30 (d, 1H) 6.64 (d, 1H)

Example 33: Preparation of 4-methyl-5-pyrimidin-2-yl-pyridazine

(242) ##STR00131##

Step 1: Preparation of 2-(5-methyl-1,4-dihydropyridazin-4-yl)pyrimidine

(243) ##STR00132##

(244) A solution of 2-pyridazin-4-ylpyrimidine (2 g) in tetrahydrofuran (20 mL), under nitrogen atmosphere, was cooled to 0° C. and to this was added methylmagnesium chloride (3M in tetrahydrofuran, 8.4 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine (2×), dried over anhydrous sodium sulfate and concentrated to give crude 2-(5-methyl-1,4-dihydropyridazin-4-yl)pyrimidine, which was used without further purification

Step 2: Preparation of 4-methyl-5-pyrimidin-2-yl-pyridazine

(245) To a solution of 2-(5-methyl-1,2-dihydropyridazin-4-yl)pyrimidine (1 g) in dichloromethane (20 mL), under nitrogen atmosphere, was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.61 g) and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified on silica using 20% methanol in dichloromethane as eluent. The resulting solid was triturated with ethyl acetate to give 4-methyl-5-pyrimidin-2-yl-pyridazine.

(246) 1H NMR (400 MHz, d.sub.6-DMSO) 9.54 (m, 1H) 9.28-9.31 (m, 1H) 9.02-9.07 (m, 2H) 7.60-7.68 (m, 1H) 2.62 (s, 3H)

Example 34: Preparation of 3-[4-(5-chloro-6-oxo-1H-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoic Acid 2,2,2-trifluoroacetate A161

(247) ##STR00133##

Step 1: Preparation of ethyl 3-[4-(5-chloro-4-methoxy-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoate

(248) ##STR00134##

(249) To a mixture of 5-chloro-4-methoxy-2-pyridazin-4-yl-pyrimidine (0.4 g) in acetonitrile (4 mL), under nitrogen atmosphere, was added ethyl 3-bromopropanoate (0.346 mL). The mixture was heated at 60° C. for 48 hours and concentrated to give crude ethyl 3-[4-(5-chloro-4-methoxy-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoate bromide, which was used without further purification.

Step 2: Preparation of 3-[4-(5-chloro-6-oxo-1H-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoic Acid; 2,22-trifluoroacetate A161

(250) A mixture of ethyl 3-[4-(5-chloro-4-methoxy-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoate (0.88 g) and 2M aqueous hydrochloric acid (8.8 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 3-[4-(5-chloro-6-oxo-1H-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate.

(251) 1H NMR (400 MHz, D.sub.2O) 9.95 (s, 1H) 9.87 (d, 1H) 9.00 (dd, 1H) 8.44 (s, 1H) 5.09 (t, 2H) 3.22 (t, 2H) (one NH proton and one CO.sub.2H proton missing)

Example 35: Preparation of 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A184

(252) ##STR00135##

Step 1: Preparation of 2,2-dimethylpropyl Methanesulfonate

(253) ##STR00136##

(254) A solution of triethylamine (8.1 mL) and 2,2-dimethylpropan-1-ol (2.3 g) in dichloromethane (40 mL) was cooled to 0° C. in an ice/acetone bath. To this was added methanesulfonyl chloride (2.2 mL) drop wise. The reaction mixture was stirred cold for 2 hours and washed with aqueous ammonium chloride. The organic layer was concentrated and the residue dissolved in ether. The ether solution was passed through a plug of silica eluting with further ether. Concentration of the ether filtrate gave 2,2-dimethylpropyl methanesulfonate as a light yellow liquid.

(255) 1H NMR (400 MHz, CDCl.sub.3) 3.90-3.85 (m, 2H) 3.01 (s, 3H) 1.00 (s, 9H)

Step 2: Preparation of 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate

(256) ##STR00137##

(257) A solution of 2,2-dimethylpropyl methanesulfonate (1.75 g) in tetrahydrofuran (22.1 mL) was cooled to −78° C. under nitrogen atmosphere. To this was added drop wise n-butyllithium (2.5 mol/L in hexane, 5.1 mL). The reaction mixture was gradually warmed to −30° C. over 2 hours and acetone (7.73 mL) was added. The reaction mixture was warmed to room temperature and stirred for a further 1.5 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate (×3). The combined organic extracts were dried with magnesium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in iso-hexane to give 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate as a colourless liquid.

(258) 1H NMR (400 MHz, CDCl.sub.3) 3.90 (s, 2H) 3.32 (s, 2H) 2.79 (br s, 1H) 1.44 (s, 6H) 0.99 (s, 9H)

Step 3: Preparation of 2-hydroxy-2-methyl-propane-1-sulfonic Acid

(259) ##STR00138##

(260) A mixture of 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate (1.84 g) and 6M aqueous hydrochloric acid (32.8 mL) was heated at 95° C. for 4 hours. The reaction mixture was cooled to room temperature and freeze dried overnight to give 2-hydroxy-2-methyl-propane-1-sulfonic acid as an off white solid.

(261) 1H NMR (400 MHz, D.sub.2O) 2.99 (s, 2H) 1.24 (s, 6H) (one OH proton and one SO.sub.3H proton missing)

Step 4: Preparation of 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A184

(262) A mixture of 2-pyridazin-4-ylpyrimidine (0.507 g) in dry acetonitrile (32.1 mL) was cooled in an ice bath. To this was added 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (0.663 mL) and the reaction mixture stirred at room temperature for 15 minutes. To this was added triphenylphosphine (1.68 g) and a solution of 2-hydroxy-2-methyl-propane-1-sulfonic acid (0.741 g) in dry acetonitrile (0.5 mL) followed by drop wise addition of diisopropyl azodicarboxylate (1.26 mL, 1.30 g). The reaction mixture was then heated at 80° C. for 144 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous layer purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate as a yellow solid.

(263) 1H NMR (400 MHz, CD.sub.3OD) 10.41-10.35 (m, 1H) 10.05-9.99 (m, 1H) 9.31 (dd, 1H) 9.12 (d, 2H) 7.67 (t, 1H) 3.67 (s, 2H) 2.10 (s, 6H)

Example 36: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A181

(264) ##STR00139##

Step 1: Preparation of 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate

(265) ##STR00140##

(266) A solution of 2,2-dimethylpropyl methanesulfonate (2 g) in tetrahydrofuran (25 mL) was cooled to −78° C. under nitrogen atmosphere and n-butyllithium (2.5 mol/L in hexane, 5.8 mL) was added drop wise. The reaction mixture was gradually warmed to −30° C. over 1 hour and acetaldehyde (6.8 mL) was added. The reaction mixture was warmed to room temperature and stirred for a further 2.5 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate (×3). The combined organic extracts were dried with magnesium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in iso-hexane to give 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate as a yellow liquid.

(267) 1H NMR (400 MHz, CDCl.sub.3) 4.47-4.34 (m, 1H) 3.96-3.87 (m, 2H) 3.25-3.17 (m, 2H) 3.01 (br s, 1H) 1.34 (d, 3H) 1.00 (s, 9H)

Step 2: Preparation of 2-hydroxypropane-1-sulfonic Acid

(268) ##STR00141##

(269) A mixture of 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate (1.35 g) and 6M aqueous hydrochloric acid (32.8 mL) was heated at 95° C. for 4 hours. The reaction mixture was cooled to room temperature and freeze dried overnight to give 2-hydroxypropane-1-sulfonic acid as a brown solid.

(270) 1H NMR (400 MHz, D.sub.2O) 4.17-4.06 (m, 1H) 2.99-2.85 (m, 2H) 1.16 (d, 3H) (one OH proton and one SO.sub.3H proton missing)

Step 3: Preparation of 2-(trifluoromethylsulfonyloxy)propane-1-sulfonic Acid

(271) ##STR00142##

(272) To a mixture of 2-hydroxypropane-1-sulfonic acid (0.2 g) in dichloromethane (2.57 mL) was added 2,6-dimethylpyridine (0.33 mL) and the resulting mixture was cooled to 0° C. To this was added drop wise trifluoromethylsulfonyl trifluoromethanesulfonate (0.264 mL) and stirring continued at this temperature for 15 minutes. Cooling was removed and the reaction mixture was stirred at room temperature for a further hour. The reaction mixture was quenched with water and extracted with dichloromethane (×3). The combined organic extracts were dried with magnesium sulfate and concentrated to give 2-(trifluoromethylsulfonyloxy)propane-1-sulfonic acid as a brown gum, ˜50% purity. The product was used immediately in subsequent reactions without further purification.

(273) 1H NMR (400 MHz, CDCl.sub.3) product peaks only 5.57-5.41 (m, 1H) 4.18-3.98 (m, 1H) 3.58-3.35 (m, 1H) 1.76-1.65 (m, 3H) (one SO.sub.3H proton missing)

Step 4: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A181

(274) A mixture of 2-pyridazin-4-ylpyrimidine (0.15 g), 2-(trifluoromethylsulfonyloxy)propane-1-sulfonate (0.55 g) and 1,4-dioxane (7.8 mL) was heated at 90° C. for 24 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous layer purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate as a yellow solid.

(275) 1H NMR (400 MHz, CD.sub.3OD) 10.43-10.37 (m, 1H) 9.93 (dd, 1H) 9.34 (dd, 1H) 9.11 (d, 2H) 7.68 (t, 1H) 5.66-5.53 (m, 1H) 3.66 (dd, 1H) 3.43 (dd, 1H) 1.83 (d, 3H)

Example 37: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanol 2,2,2-trifluoroacetate A195

(276) ##STR00143##

Step 1: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl Sulfate A194

(277) ##STR00144##

(278) A mixture of 2-pyridazin-4-ylpyrimidine (0.2 g), 1,2-dichloroethane (3.8 mL) and 1,3,2-dioxathiolane 2,2-dioxide (0.198 g) was stirred at room temperature for 22 hours. The resulting precipitate was filtered off and washed with dichloromethane to give a mixture of regio-isomers. This mixture was triturated with water and filtered to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl sulfate as a pale grey solid.

(279) 1H NMR (400 MHz, D.sub.2O) 10.28 (d, 1H) 9.87 (d, 1H) 9.29 (dd, 1H) 9.07 (d, 2H) 7.72 (t, 1H) 5.18-5.28 (m, 2H) 4.62-4.72 (m, 2H)

Step 2: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanol 2,2,2-trifluoroacetate A195

(280) A mixture of crude 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl sulfate (0.25 g, mixture of regio-isomers) and 2M aqueous hydrochloric acid (5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated, washed with cyclohexane and tert-butylmethylether and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanol 2,2,2-trifluoroacetate.

(281) 1H NMR (400 MHz, D.sub.2O) 10.25 (d, 1H) 9.81 (d, 1H) 9.26 (dd, 1H) 9.05 (d, 2H) 7.70 (t, 1H) 4.94-5.08 (m 2H) 4.17-4.22 (m 2H)

Example 38: Preparation of 3-[4-(5-carbamoylpyrazin-2-yl)pyridazin-1-ium-1-yl]propanoic Acid 2,2,2-trifluoroacetate A202

(282) ##STR00145##

(283) A mixture of ethyl 3-[4-(5-cyanopyrazin-2-yl)pyridazin-1-ium-1-yl]propanoate bromide (0.33 g) and 2M aqueous hydrochloric acid (5 mL) was stirred at room temperature for 40 hours. The reaction mixture was concentrated, washed with cyclohexane and tert-butylmethylether and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 3-[4-(5-carbamoylpyrazin-2-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate.

(284) 1H NMR (400 MHz, D.sub.2O) 10.18 (d, 1H) 9.92 (d, 1H) 9.51 (d, 1H) 9.43 (d, 1H) 9.20 (dd, 1H) 5.18 (t, 2H) 3.31 (t, 2H) (two NH protons and one C.sub.02H proton missing)

Example 39: Preparation of [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate A201

(285) ##STR00146##

(286) Step 1: Preparation of [(1S)-3-bromo-1-methoxycarbonyt-propyl]ammonium chloride

(287) ##STR00147##

(288) To a mixture of (2S)-2-amino-4-bromo-butanoic acid (0.2 g) in dry methanol (4 mL) at 0° C., under nitrogen atmosphere, was added thionyl chloride (0.392 g) drop wise. The reaction mixture was stirred overnight at room temperature and concentrated to give crude [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride as an orange gum, which was used without further purification.

Step 2: Preparation of methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate

(289) ##STR00148##

(290) Crude [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride was stirred in dichloromethane (4 mL) and a solution of sodium hydrogen carbonate (0.28 g) in water (4 mL) was added. The mixture was cooled to 0° C. and benzyl carbonochloridate (0.225 g) was added. The reaction mass was warmed to room temperature and stirred for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in cyclohexane to give methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate.

(291) 1H NMR (400 MHz, CDCl.sub.3) 7.30-7.40 (m, 5H) 5.37-5.43 (m, 1H) 5.13 (s, 2H) 3.78 (s, 3H) 3.42-3.46 (m, 2H) 2.25-2.49 (m, 2H)

Step 3: Preparation of Methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate Iodide

(292) ##STR00149##

(293) To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate (0.1 g) in dry acetone (2 mL), under nitrogen atmosphere, was added sodium iodide (0.054 g). The reaction mixture was stirred at room temperature overnight. To this was added 2-pyridazin-4-ylpyrimidine (0.048 g) and the mixture heated at reflux for 16 hours. The reaction mixture was concentrated and the crude methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate iodide was used in the next step without further purification.

Step 4: Preparation of [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate A201

(294) A mixture of methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate iodide (0.5 g) and concentrated hydrochloric acid (4.9 mL) was heated at 80° C. for 30 minutes. The reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate (3×20 mL). The aqueous layer was purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate.

(295) 1H NMR (400 MHz, D.sub.2O) 10.26 (d, 1H) 9.90 (d, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 5.17 (t, 2H) 4.09 (dd, 1H) 2.76-2.79 (m, 2H) (Three NH protons and one C.sub.02H proton missing)

Example 40: Preparation of [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate A207

(296) ##STR00150##

Step 1: Preparation of [(1R)-3-bromo-1-methoxycarbonyl-propyl]ammonium Chloride

(297) ##STR00151##

(298) To a mixture of [(1R)-3-bromo-1-carboxy-propyl]ammonium bromide (0.1 g) in dry methanol (2 mL) at 0° C., under nitrogen atmosphere, was added thionyl chloride (0.083 mL) drop wise. The reaction mixture was stirred overnight at room temperature and concentrated to give crude [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride as a yellow solid, which was used without further purification.

Step 2: Preparation of [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium Bromide Chloride

(299) ##STR00152##

(300) To a mixture of 2-pyridazin-4-ylpyrimidine (0.1 g) in acetonitrile (3.16 mL) was added [(1R)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride (0.16 g) The mixture was heated at reflux for 12 hours. The reaction mixture was concentrated to give crude [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium bromide as a dark brown gum, which was used without further purification.

Step 3: Preparation of [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate A207

(301) A mixture of [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium bromide (0.5 g) and 2M aqueous hydrochloric acid (7.29 mL) was heated at 80° C. for 2 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate.

(302) 1H NMR (400 MHz, D.sub.2O) 10.22 (s, 1H) 9.87 (d, 1H) 9.24 (d, 1H) 8.99-9.04 (m, 2H) 7.66 (t, 1H) 5.16 (t, 2H) 4.17 (dd, 1H) 2.69-2.85 (m, 2H) (Three NH protons and one C.sub.02H proton missing)

Example 41: Preparation of hydroxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate A205

(303) ##STR00153##

Step 1: Preparation of 1-(diethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium 2,2,2-trifluoroacetate A230

(304) ##STR00154##

(305) To a solution of diethoxyphosphorylmethanol (0.2 g) in dichloromethane (3.57 mL) at −78° C., under nitrogen atmosphere, was added N,N-diisopropylethylamine (0.244 mL) followed by trifluoromethylsulfonyl trifluoromethanesulfonate (0.24 mL). The reaction was warmed slowly to 0° C. over 2 hours. To this mixture was added a solution of 2-pyridazin-4-ylpyrimidine (0.188 g) in dichloromethane (3.57 mL) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, diluted with ethanol, concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 1-(diethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium 2,2,2-trifluoroacetate as a brown gum.

(306) 1H NMR (400 MHz, d.sub.6-DMSO) 10.39-10.35 (m, 1H) 10.01 (d, 1H) 9.47 (dd, 1H) 9.22 (d, 2H) 7.84 (t, 1H) 5.78 (d, 2H) 4.24-4.13 (m, 4H) 1.27 (t, 6H)

Step 2: Preparation of hydroxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate A205

(307) To a mixture of 1-(diethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium 2,2,2-trifluoroacetate (0.17 g) in dry acetonitrile (7.42 mL) at room temperature, under nitrogen atmosphere, was added bromo(trimethyl)silane (0.049 mL). After stirring overnight further bromo(trimethyl)silane (0.049 mL) was added After stirring overnight again a final portion of bromo(trimethyl)silane (0.049 mL) was added. After stirring overnight the reaction mixture was quenched with water and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give hydroxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate as an off white solid.

(308) 1H NMR (400 MHz, D.sub.2O) 10.16-10.13 (m, 1H) 9.72-9.68 (m, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (d, 2H) (one OH proton missing)

Example 42: Preparation of [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]ammonium 2,2,2-trifluoroacetate A208

(309) ##STR00155##

Step 1: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate

(310) ##STR00156##

(311) To a mixture of 2-pyridazin-4-ylpyrimidine (0.05 g) in dry acetonitrile (1 mL) was added tert-butyl N-[(3S)-2-oxooxetan-3-yl]carbamate (0.071 g) and the reaction mixture was stirred at room temperature for 48 hours. Concentration of the reaction mixture gave crude (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate, which was used without further purification.

Step 2: Preparation of [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]ammonium 2,2,2-trifluoroacetate A208

(312) A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate (0.4 g) and 2M aqueous hydrochloric acid (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]ammonium 2,2,2-trifluoroacetate.

(313) 1H NMR (400 MHz, D.sub.2O) 10.26 (s, 1H) 9.94 (d, 1H) 9.31-9.34 (m, 1H) 9.04 (dd, 2H) 7.69 (t, 1H) 5.48 (d, 2H) 4.75 (t, 1H) (Three NH protons and one CO2H proton missing)

Example 43: Preparation of N-methyl-2-pyridazin-4-yl-pyrimidine-5-sulfonamide

(314) ##STR00157##

Step 1: Preparation of 2-chloro-N-methyl-pyrimidine-5-sulfonamide

(315) ##STR00158##

(316) Cooled a solution of 2-chloropyrimidine-5-sulfonyl chloride (0.05 g) in tetrahydrofuran (1 mL) at −78° C., under nitrogen atmosphere, and added methanamine (2M in tetrahydrofuran, 0.117 mL) followed by N,N-diisopropylethylamine (0.065 mL). The reaction was stirred for 20 minutes and quenched with ice cold water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated to give crude 2-chloro-N-methyl-pyrimidine-5-sulfonamide.

(317) 1H NMR (400 MHz, d.sub.6-DMSO) 9.10 (s, 2H) 7.96-8.00 (m, 1H) 2.54 (d, 3H)

Step 2: Preparation of N-methyl-2-pyridazin-4-yl-pyrimidine-5-sulfonamide

(318) A microwave vial, under nitrogen atmosphere, was charged with tributyl(pyridazin-4-yl)stannane (0.64 g), 2-chloro-N-methyl-pyrimidine-5-sulfonamide (0.3 g), palladium (0) tetrakis(triphenylphosphine) (0.167 g) and 1,4-dioxane (4.5 mL) and heated at 130° C. in the microwave for 30 minutes. The reaction mixture was concentrated and triturated with tert-butylmethylether to give N-methyl-2-pyridazin-4-yl-pyrimidine-5-sulfonamide as a black solid.

(319) 1H NMR (400 MHz, d.sub.6-DMSO) 10.03-10.04 (m, 1H) 9.53-9.54 (m, 1H) 9.35 (s, 2H) 8.49-8.51 (m, 1H) 8.04-8.05 (m, 1H) 2.58 (d, 3H)

Example 44: Preparation of 2-(6-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate A212

(320) ##STR00159##

Step 1: Preparation of 3-methyl-5-pyrimidin-2-yl-1H-pyridazin-6-one

(321) ##STR00160##

(322) To a mixture of 5-bromo-3-methyl-1H-pyridazin-6-one (0.1 g) in degassed 1,4-dioxane (2 mL), under nitrogen atmosphere, was added tributyl(pyrimidin-2-yl)stannane (0.234 g), dichloropalladium triphenylphosphane (0.038 g) and cuprous iodide (0.02 g) and the mixture heated at 130° C. for 2 hours. The reaction mixture was diluted with 1,4-dioxane, filtered, using a syringe filter, to remove insoluble material and purified on silica using a gradient from 0 to 10% methanol in dichloromethane to give 3-methyl-5-pyrimidin-2-yl-1H-pyridazin-6-one as a white solid.

(323) 1H NMR (400 MHz, d.sub.6-DMSO) 12.90-13.20 (br s, 1H) 8.92-8.93 (m, 2H) 7.68 (s, 1H) 7.53-7.54 (m, 1H) 2.31 (s, 3H)

Step 2: Preparation of 3-chloro-6-methyl-4-pyrimidin-2-yl-pyridazine

(324) ##STR00161##

(325) A mixture of 3-methyl-5-pyrimidin-2-yl-1H-pyridazin-6-one (1.93 g) and phosphorus oxychloride (1.93 mL) was heated at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated, poured onto ice and basified with a cold aqueous sodium bicarbonate solution to pH 8. The aqueous was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×40 mL), dried over sodium sulphate and concentrated to give 3-chloro-6-methyl-4-pyrimidin-2-yl-pyridazine.

(326) 1H NMR (400 MHz, CDCl.sub.3) 8.94-8.95 (m 2H) 7.78 (s, 1H) 7.42-7.44 (m, 1H) 2.80 (s, 3H)

Step 3: Preparation of 3-methyl-5-pyrimidin-2-yl-pyridazine

(327) ##STR00162##

(328) Triethylamine (1.32 mL) was added to a solution of 3-chloro-6-methyl-4-pyrimidin-2-yl-pyridazine (1.5 g) in a mixture of ethanol (40 mL) and ethyl acetate (10 mL). This mixture was degassed with nitrogen and 10% palladium on carbon (0.2 g) was added. This mixture was hydrogenated under a balloon atmosphere of hydrogen for 1 hour at room temperature. Further catalyst (0.2 g) was added and hydrogenation continued for an additional 3 hours. The reaction mixture was diluted with ethanol (50 mL) and filtered through Celite, washing with ethanol (2×40 mL). The filtrate was concentrated and purified on silica using a gradient from 0 to 10% methanol in dichloromethane to give 3-methyl-5-pyrimidin-2-yl-pyridazine as a white solid.

(329) 1H NMR (400 MHz, CDCl.sub.3) 9.97 (d, 1H) 8.89 (d, 2H) 8.27 (d, 1H) 7.35-7.38 (m, 1H) 2.82 (s, 3H)

Step 4: Preparation of 2-(6-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate A212

(330) A mixture of 3-methyl-5-pyrimidin-2-yl-pyridazine (0.8 g) and sodium 2-bromoethanesulfonate (1.078 g) in water (16 mL) was heated at 120° C. for 24 hours. The reaction mixture was concentrated, washed with tert-butylmethylether and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-(6-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate.

(331) 1H NMR (400 MHz, D.sub.2O) 10.00 (d, 1H) 9.08 (d, 1H) 9.00 (d, 2H) 7.65 (t, 1H) 5.16 (t, 2H) 3.68 (t, 2H) 3.12 (s, 3H)

Example 45: Preparation of dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetyl]azanide A214

(332) ##STR00163##

Step 1: Preparation of 2-bromo-N-(dimethylsulfamoyl)acetamide

(333) ##STR00164##

(334) To a solution of dimethylsulfamide (0.5 g) and 4-(dimethylamino)pyridine (0.541 g) in dichloromethane (19.9 mL) at 0° C. was added bromoacetyl bromide (0.903 g) drop wise. The reaction was slowly warmed to room temperature and stirred for 24 hours. The reaction was partitioned with 0.5M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated to give crude 2-bromo-N-(dimethylsulfamoyl)acetamide as a pale yellow oil. The product was used without further purification.

Step 2: Preparation of dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetyl]azanide A214

(335) To a solution of 2-pyridazin-4-ylpyrimidine (0.15 g) in acetonitrile (10 mL) was added 2-bromo-N-(dimethylsulfamoyl)acetamide (0.21 g) and the mixture heated at 80° C. for 16 hours. The resulting precipitate was filtered, washed with acetonitrile (2×20 mL) to give dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetyl]azanide as a light green solid.

(336) 1H NMR (400 MHz, d.sub.6-DMSO) 10.36 (s, 1H) 10.06-10.10 (m, 1H) 9.56-9.62 (m, 1H) 9.18-9.22 (m, 2H) 7.82-7.86 (m, 1H) 5.88-5.94 (m, 2H) 2.80-2.86 (m, 6H)

Example 46: Preparation of N-(2-bromoethyl)-1,1,1-trifluoro-methanesulfonamide

(337) ##STR00165##

(338) A mixture of 2-bromoethanamine bromide (1 g) and N,N-diisopropylethylamine (1.42 g) was stirred in dichloromethane (24.5 mL) at 0° C. until the reaction became homogeneous. Trifluoromethanesulfonic anhydride (1.55 g) was added drop wise and stirred at 0° C. for 3 hours. The reaction mixture was concentrated and partitioned between 1M aqueous hydrochloric acid and diethyl ether. The organic layer was washed with water, 1M aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated to afford N-(2-bromoethyl)-1,1,1-trifluoro-methanesulfonamide as a pale yellow oil.

(339) 1H NMR (400 MHz, CDCl.sub.3) 5.44 (br. s., 1H) 3.71 (q, 2H) 3.53 (t, 2H).

Example 47: Preparation of 2-bromo-N-methoxy-acetamide

(340) ##STR00166##

(341) To a suspension of methoxyamine hydrochloride (0.248 g) and N,N-diisopropylethylamine (2.29 mL) in tetrahydrofuran (10 mL) at 0° C. was added 2-bromoacetyl bromide (0.5 g) drop wise. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated and purified on silica using 2:1 iso-hexane:ethyl acetate to give 2-bromo-N-methoxy-acetamide as a pale yellow liquid.

(342) 1H NMR (400 MHz, CDCl.sub.3) 4.48 (s, 2H) 4.24-4.28 (m, 1H) 3.88-3.92 (m 3H)

Example 48: Preparation of 3-bromo-N-cyano-propanamide

(343) ##STR00167##

(344) To a stirred solution of cyanamide (0.5 g) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C. was added sodium hydroxide (1.427 g). After 10 minutes at 0° C. a solution of 3-bromopropanoyl chloride (1.27 mL) in tetrahydrofuran (5 mL) was added drop wise. The resulting reaction mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with dichloromethane (2×75 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-bromo-N-cyano-propanamide as a light yellow liquid.

(345) 1H NMR (400 MHz, de-DMSO) 12.40 (br s, 1H) 3.54-3.70 (m, 2H) 2.80-2.94 (m, 2H)

Example 49: Preparation of [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium Dichloride A211

(346) ##STR00168##

Step 1: Preparation of dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate

(347) ##STR00169##

(348) To a solution of dimethyl (2S)-2-(tert-butoxycarbonylamino)pentanedioate (0.3 g) in acetonitrile (6 mL), under nitrogen atmosphere, was added 4-dimethylaminopyridine (0.028 g). The mixture was cooled to 0° C. and di-tert-butyl dicarbonate (0.264 g) was added. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was partitioned between water and ethyl acetate (80 mL) and extracted with further ethyl acetate (80 mL). The combined organic layers were washed with 10% aqueous citric acid, followed by saturated sodium bicarbonate solution and brine. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica using ethyl acetate in cyclohexane to give dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate as a colourless gum.

(349) 1H NMR (400 MHz, CDCl.sub.3) 4.95 (dd, 1H) 3.73 (s, 3H) 3.68 (s, 3H) 2.36-2.54 (m 3H) 2.15-2.23 (m, 1H) 1.50 (s, 18H)

Step 2: Preparation of Methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate

(350) ##STR00170##

(351) Cooled a solution of dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate (0.28 g) in diethyl ether (5.6 mL), under nitrogen atmosphere, to −78° C. and added slowly diisobutylaluminum hydride (1M in Toluene, 0.82 mL). The reaction was stirred at −78° C. for 10 minutes, then quenched with water (0.094 mL) and stirred for a further 30 minutes. After warming to room temperature solid sodium sulfate was added. The mixture was filtered through Celite, washed with tert-butylmethylether and the filtrate concentrated to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate.

(352) 1H NMR (400 MHz, CDCl.sub.3) 9.78 (s, 1H) 4.90 (dd, 1H) 3.73 (m, 3H) 2.45-2.66 (m, 3H) 2.11-2.28 (m, 1H) 1.42-1.63 (m, 18H)

Step 3: Preparation of Methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate

(353) ##STR00171##

(354) Cooled a solution of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate (0.2 g) in dry methanol (4 mL), under nitrogen atmosphere, to 0° C. and added sodium borohydride (0.025 g) portion wise and stirred for 2 hours. The reaction mixture was concentrated and purified on silica using ethyl acetate in cyclohexane to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate as a colourless gum.

(355) 1H NMR (400 MHz, CDCl.sub.3) 4.90 (dd, 1H) 3.74-3.67 (m, 5H) 2.30-2.20 (m, 1H) 1.99-1.89 (m, 1H) 1.68-1.41 (s, 20H) (one OH proton missing)

Step 4: Preparation of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate

(356) ##STR00172##

(357) Cooled a solution of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate (4 g) in dry tetrahydrofuran (40 mL) to 0° C. and added carbon tetrabromide (5.728 g). To this was added drop wise a solution of triphenylphosphine (4.576 g) in tetrahydrofuran (40 mL). The reaction was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was concentrated and purified on silica using ethyl acetate in cyclohexane to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate.

(358) 1H NMR (400 MHz, CDCl.sub.3) 4.88 (dd, 1H) 3.73 (s, 3H) 3.38-3.50 (m, 2H) 2.24-2.27 (m, 1H) 1.85-2.12 (m, 3H) 1.51 (s, 18H)

Step 5: Preparation of [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium 2,2,2-trifluoroacetate

(359) ##STR00173##

(360) To a mixture of 2-pyridazin-4-ylpyrimidine (0.4 g) in acetonitrile (12.6 mL) was added methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate (1.141 g) and the reaction mixture was heated at reflux for 12 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent which led to the loss of the BOC-protecting groups) to give [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium 2,2,2-trifluoroacetate.

(361) 1H NMR (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.80-9.86 (m, 1H) 9.20-9.27 (m, 1H) 8.99-9.06 (m, 2H) 7.66-7.73 (m, 1H) 4.90-5.01 (m, 2H) 4.20 (t, 1H) 3.76-3.84 (m, 3H) 2.20-2.40 (m, 2H) 1.97-2.18 (m, 2H) (NH protons are missing)

Step 6: Preparation of [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium dichloride A211

(362) A mixture of [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium; 2,2,2-trifluoroacetate (0.1 g) and 4M aqueous hydrochloric acid (0.78 mL) was heated at 60° C. for 14 hours. The reaction mixture was concentrated to give [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium dichloride.

(363) 1H NMR (400 MHz, D.sub.2O) 10.24 (dd, 1H) 9.87 (dd, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 4.99 (t, 2H) 4.08 (t, 1H) 2.23-2.44 (m, 2H) 2.00-2.16 (m, 2H) (three NH protons and one C.sub.02H proton missing)

Example 50: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic Acid Chloride A26

(364) ##STR00174##

Step 1: Preparation of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate A54

(365) ##STR00175##

(366) A mixture of methyl 3-bromopropanoate (1.58 g), 2-pyridazin-4-ylpyrimidine (0.5 g) in acetonitrile (31.6 mL) was heated at 80° C. for 24 hours. The reaction mixture was cooled, concentrated and partitioned between water (10 mL) and dichloromethane (20 mL). The aqueous layer was purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate as an orange gum.

(367) .sup.1H NMR (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.98 (d, 2H) 7.63 (t, 1H) 5.12 (t, 2H) 3.59 (s, 3H) 3.25 (t, 2H)

(368) .sup.1H NMR (400 MHz, CD.sub.3OD) 10.43-10.32 (m, 1H) 10.04 (d, 1H) 9.43 (dd, 1H) 9.12 (d, 2H) 7.65 (t, 1H) 5.18 (t, 2H) 3.70 (s, 3H) 3.36-3.27 (m, 2H)

Step 2: 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic Acid Chloride A26

(369) A mixture of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate; 2,2,2-trifluoroacetate (0.392 g) and conc. hydrochloric acid (7.66 mL) was heated at 80° C. for 3 hours. The reaction mixture was cooled, concentrated and triturated with acetone to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride as a beige solid.

(370) .sup.1H NMR (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one C.sub.02H proton missing)

(371) .sup.1H NMR (400 MHz, CD.sub.3OD) 10.43-10.32 (m, 1H) 10.02 (d, 1H) 9.36 (dd, 1H) 9.09 (d, 2H) 7.68 (t, 1H) 5.16 (t, 2H) 3.29-3.21 (m, 2H) (one C.sub.02H proton missing)

Example 51: Preparation of methoxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate A245

Step 1: Preparation of Dimethoxyphosphorylmethyl Trifluoromethanesulfonate

(372) ##STR00176##

(373) A solution of dimethoxyphosphorylmethanol (1 g) in dichloromethane (20 mL) was cooled to −78° C. and 2,6-Lutidine (1.32 mL) followed by trifluoromethylsulfonyl trifluoromethanesulfonate (1.91 g) was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane (50 mL). The organic layer was washed with 1M aqueous hydrochloric acid (50 mL), dried over anhydrous sodium sulfate and concentrated to give dimethoxyphosphorylmethyl trifluoromethanesulfonate as a pale yellow liquid.

(374) 1H NMR (400 MHz, d.sub.6-DMSO) 4.82 (d, 2H) 3.78 (s, 3H) 3.74 (s, 3H)

Step 2: Preparation of 1-(dimethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium trifluoromethanesulfonate A238

(375) ##STR00177##

(376) To a stirred solution of 2-pyridazin-4-ylpyrimidine (0.6 g) in acetonitrile (15 mL) was added dimethoxyphosphorylmethyl trifluoromethanesulfonate (1.549 g) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the obtained residue was partitioned between water (75 mL) and dichloromethane (75 mL). The aqueous layer was washed with further dichloromethane (75 mL), concentrated and purified by Reverse Phase chromatography using 100% water (note: no added trifluoroacetic acid) to give 1-(dimethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium trifluoromethanesulfonate as a brown liquid

(377) 1H NMR (400 MHz, D.sub.2O) 10.37 (d, 1H) 10.00 (d, 1H) 9.48-9.42 (m, 1H) 9.23-9.20 (m, 2H) 7.83 (t, 1H) 5.82 (d, 2H) 3.83 (s, 3H) 3.82-3.78 (m, 3H)

Step 3: Preparation of methoxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate A245

(378) ##STR00178##

(379) To a stirred solution of 1-(dimethoxyphosphorymethyl)-4-pyrimidin-2-yl-pyridazin-1-ium trifluoromethanesulfonate (0.1 g) in dichloromethane (10 mL) was added bromotrimethylsilane (0.097 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was dissolved in water (25 mL) and washed with dichloromethane (2×25 mL). The aqueous layer was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give methoxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate as a light brown solid.

(380) 1H NMR (400 MHz, D.sub.2O) 10.19-10.15 (m, 1H) 9.73-9.69 (m, 1H) 9.25-9.20 (m, 1H) 9.01 (d, 2H) 7.68-7.62 (m, 1H) 5.19 (d, 2H) 3.61 (d, 3H)

(381) Additional compounds in Table A (below) were prepared by analogues procedures, from appropriate starting materials. The skilled person would understand that the compounds of Formula (I) may exist as an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion as described hereinbefore. Where mentioned the specific counterion is not considered to be limiting, and the compound of Formula (I) may be formed with any suitable counter ion.

(382) NMR spectra contained herein were recorded on either a 400 MHz Bruker AVANCE III HD equipped with a Bruker SMART probe unless otherwise stated. Chemical shifts are expressed as ppm downfield from TMS, with an internal reference of either TMS or the residual solvent signals. The following multiplicities are used to describe the peaks: s=singlet, d=doublet, t=triplet, dd=double doublet, dt=double triplet, q=quartet, quin=quintet, m=multiplet. Additionally br. is used to describe a broad signal and app. is used to describe and apparent multiplicity.

(383) Additional compounds in Table A were prepared by analogous procedures, from appropriate starting materials.

(384) TABLE-US-00011 TABLE A Physical Data for Compounds of the Invention Compound Number Structure .sup.1H NMR A1 (400 MHz, D.sub.2O) 10.19 (d, 1H) 9.84 (d, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.27-5.18 (m, 2H) 3.71-3.63 (m, 2H) A2 0 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.84 (d, 1H) 9.30 (dd, 1H) 9.01 (d, 2H) 7.66 (t, 1H) 5.84 (s, 2H) 3.79 (s, 3H) A3 (400 MHz, D.sub.2O) 10.26 (brs, 1H) 9.94 (br d, 1H) 9.27-9.39 (m, 1H) 8.96-9.14 (m, 2H) 7.56-7.73 (m, 1H) 5.97 (s, 2H) A4 (400 MHz, D.sub.2O) 10.09 (d, 1H) 9.87 (d, 1H) 9.35 (d, 1H) 9.12 (dd, 1H) 9.04 (d, 1H) 8.29 (dd, 1H) 5.24 (t, 2H) 3.67 (t, 2H) A5 (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.87 (d, 1H) 9.33 (dd, 1H) 9.12 (dd, 1H) 8.52 (dd, 1H) 7.99 (dd, 1H) 5.32-5.19 (m, 2H) 3.73-3.65 (m, 2H) A6 (400 MHz, D.sub.2O) 10.18 (d, 1H) 9.80 (d, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.01 (t, 2H) 2.98 (t, 2H) 2.53 (quin, 2H) A7 (400 MHz, D.sub.2O) 10.08 (d, 1H) 9.79 (d, 1H) 9.39 (d, 1H) 9.08 (dd, 1H) 8.89-8.83 (m, 1H) 8.78 (d, 1H) 5.24-5.16 (t, 2H) 3.65 (t, 2H) A8 (400 MHz, CD.sub.3OD) 10.32 (d, 1H) 10.02 (d, 1H) 9.65 (d, 1H) 9.34 (dd, 1H) 8.98- 8.94 (m, 1H) 8.92-8.89 (m, 1H) 5.22- 5.12 (m, 2H) 4.22-4.11 (m, 4H) 2.87- 2.76 (m, 2H) 1.38-1.31 (m, 6H) A9 (400 MHz, CD.sub.3OD) 10.28 (d, 1H) 10.00 (d, 1H) 9.62 (d, 1H) 9.28 (dd, 1H) 8.96- 8.93 (m, 1H) 8.90 (d, 1H) 5.19-5.12 (t, 2H) 3.28 (t, 2H) (one CO.sub.2H proton missing) A10 (400 MHz, CD.sub.3OD) 10.27 (d, 1H) 9.93 (d, 1H) 9.63 (d, 1H) 9.28 (dd, 1H) 8.96- 8.92 (m, 1H) 8.88 (d, 1H) 5.11 (t, 2H) 2.95 (t, 2H) 2.62 (quin, 2H) A11 (400 MHz, D.sub.2O) 9.80-9.97 (m, 2H) 9.62- 9.75 (m, 1H) 9.35-9.50 (m, 1H) 8.97 (dd, 1H) 8.19-8.42 (m, 1H) 5.20-5.29 (m, 2H) 3.59-3.73 (m, 2H) A12 0 (400 MHz, D.sub.2O) 9.86-9.95 (m, 2H) 8.90- 9.00 (m, 3H) 8.35 (brd, 2H) 5.27 (t, 2H) 3.69 (t, 2H) (one NH proton missing) A13 (400 MHz, D.sub.2O) 10.28 (s, 1H) 9.88 (d, 1H) 9.27 (d, 1H) 8.71 (d, 1H) 7.10 (d, 1H) 5.29 (t, 2H) 4.13 (s, 3H) 3.74 (t, 2H) A14 (400 MHz, D.sub.2O) 10.19 (s, 1H) 9.78 (d, 1H) 9.14 (d, 1H) 8.74 (s, 2H) 5.24 (t, 2H) 4.06 (s, 3H) 3.71 (t, 2H) A15 (400 MHz, D.sub.2O) 10.39 (s, 1H) 10.01 (s, 1H) 9.57 (s, 2H) 9.44 (s, 1H) 5.23-5.50 (m, 2H) 3.70-3.85 (m, 2H) 3.45 (s, 3H) A16 (400 MHz, D.sub.2O) 10.17 (d, 1H) 10.03 (d, 1H) 9.20 (dd, 1H) 8.23 (d, 1H) 6.99 (d, 1H) 5.35 (m, 2H) 3.74 (m, 2H) 3.35 (s, 6H) A17 (400 MHz, D.sub.2O) 10.24 (d, 1H) 9.86 (d, 1H) 9.24 (dd, 1H) 9.05 (s, 2H) 5.26 (t, 2H) 3.70 (t, 2H) A18 (400 MHz, D.sub.2O) 9.98 (d, 1H) 9.45 (d, 1H) 8.81 (dd, 1H) 8.37 (s, 2H) 5.06 (t, 2H) 3.56 (t, 2H) 3.12 (s, 6H) A19 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 8.96 (s, 2H) 5.25 (t, 2H) 3.69 (t, 2H) A20 (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.96 (d, 1H) 9.13 (dd, 1H) 8.29 (d, 1H) 6.83 (d, 1H) 5.31 (m, 2H) 3.73 (m, 2H) (Two NH.sub.2 protons and one SO.sub.3H proton missing) A21 (400 MHz, D.sub.2O) 10.24 (s, 1H) 9.90 (d, 1H) 9.24 (d, 1H) 8.86 (d, 1H) 7.57 (d, 1H) 5.31 (t, 2H) 3.74 (t, 2H) 2.66 (s, 3H) A22 00 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.86 (d, 1H) 9.21 (dd, 1H) 8.90 (s, 2H) 5.25-5.31 (m, 2H) 3.69-3.77 (m, 2H) 2.44 (s, 3H) A23 01 (400 MHz, D.sub.2O) 10.30 (s, 1H) 9.90 (d, 1H) 9.32 (d, 1H) 9.29 (d, 1H) 8.04 (d, 1H) 5.25 (t, 2H) 3.68 (t, 2H) A24 02 (400 MHz, D.sub.2O) 10.31 (d, 1H) 9.94 (d, 1H) 9.33-9.38 (m, 3H) 5.26-5.31 (m, 2H) 3.69-3.73 (m, 2H) A25 03 (400 MHz, D.sub.2O) 10.35 (d, 1H) 9.97 (m, 1H) 9.45 (m, 2H) 9.36 (m, 1H) 5.30-5.36 (m, 2H) 3.73 (m, 2H) A26 04 (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) A27 05 (400 MHz, D.sub.2O) 9.87-9.97 (m, 2H) 8.92- 9.07 (m, 3H) 8.44-8.53 (m, 2H) 5.27 (t, 2H) 3.68 (dd, 2H) (one NH proton missing) A28 06 (400 MHz, CD.sub.3OD) 10.32 (d, 1H) 10.13 (d, 1H) 9.56 (s, 1H) 9.42-9.35 (m, 1H) 9.23 (d, 1H) 8.61 (d, 1H) 5.21 (t, 2H) 3.32-3.27 (m, 2H) (one CO.sub.2H proton missing) A29 07 (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.80 (d, 1H) 9.35 (d, 1H) 9.05 (dd, 1H) 8.87-8.82 (m, 1H) 8.76 (d, 1H) 5.08 (t, 2H) 3.22 (t, 2H) (one CO.sub.2H proton missing) A30 08 (400 MHz, CD.sub.3OD) 10.30-10.26 (m, 1H) 10.04-10.00 (m, 1H) 9.66-9.64 (m, 1H) 9.33-9.30 (m, 1H) 8.97-8.93 (m, 1H) 8.91-8.88 (m, 1H) 5.25-5.14 (m, 2H) 3.71-3.68 (m, 3H) 3.35-3.27 (m, 2H) A31 09 (400 MHz, D.sub.2O) 10.07 (d, 1H) 9.87 (d, 1H) 9.10 (dd, 1H) 8.95 (d, 1H) 8.13 (d, 1H) 5.24 (t, 2H) 3.67 (t, 2H) 2.78 (s, 3H) A32 0 (400 MHz, D.sub.2O) 10.26 (s, 1H) 9.86 (d, 1H) 9.26 (dd, 1H) 6.42 (s, 1H) 5.28 (t, 2H) 4.06 (s, 6H) 3.74 (t, 2H) A33 (400 MHz, D.sub.2O) 10.34 (d, 1H) 9.96 (d, 1H) 9.54 (s, 2H) 9.37 (m, 1H) 5.25 (m, 2H) 4.02 (s, 3H) 3.70 (m, 2H) A34 (400 MHz, D.sub.2O) 10.20 (m, 1H) 9.80 (m, 1H) 9.10 (m, 1H) 8.76 (s, 2H) 5.30 (m, 2H) 3.70 (m, 2H) 2.10 (m, 1H) 1.20 (m, 2H) 0.95 (m, 2H) A35 (400 MHz, D.sub.2O) 10.12 (d, 1H) 9.83 (d, 1H) 9.08 (dd, 1H) 8.42 (d, 1H) 7.89 (d, 1H) 5.28-5.19 (m, 2H) 3.71-3.64 (m, 2H) 2.74 (s, 3H) A36 (400 MHz, D.sub.2O) 10.15 (s, 1H) 9.84 (d, 1H) 9.15 (dd, 1H) 8.86 (s, 2H) 5.13 (t, 2H) 3.27 (t, 2H) 2.40 (s, 3H) (one CO.sub.2H proton missing) A37 (400 MHz, D.sub.2O) 10.20 (d, 1H) 9.91 (d, 1H) 9.22 (dd, 1H) 8.86 (d, 1H) 7.58 (d, 1H) 5.18 (t, 2H) 3.31 (t, 2H) 2.66 (s, 3H) A38 (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.79 (d, 1H) 9.12 (dd, 1H) 8.73 (s, 2H) 5.12 (t, 2H) 4.06 (s, 3H) 3.29 (t, 2H) A39 (400 MHz, D.sub.2O) 10.32 (d, 1H) 9.96 (d, 1H) 9.32-9.38 (m, 2H) 8.10 (d, 1H) 5.19 (t, 2H) 3.30 (t, 2H) A40 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.92 (d, 1H) 9.18-9.26 (m, 1H) 8.99-9.05 (m, 2H) 7.68 (t, 1H) 5.49-5.60 (m, 1H) 3.39 (dd, 1H) 3.10-3.21 (m, 1H) 1.71 (d, 3H) (One CO.sub.2H proton missing) A41 (400 MHz, D.sub.2O) 10.06 (s, 1H) 10.00 (d, 1H) 9.13 (dd, 1H) 8.28 (d, 1H) 6.85 (d, 1H) 5.20 (t, 2H) 3.31 (t, 2H) (Two NH.sub.2 protons and one CO.sub.2H proton missing) A42 0 (400 MHz, D.sub.2O) 9.93 (d, 1H) 9.53 (d, 1H) 8.80 (dd, 1H) 8.35 (s, 2H) 5.01 (t, 2H) 3.23 (t, 2H) 3.14 (s, 6H) A43 (400 MHz, D.sub.2O) 10.18 (s, 1H) 9.86 (brd, 1H) 9.21 (dd, 1H) 9.03 (s, 2H) 5.12 (t, 2H) 3.25 (t, 2H) A44 (400 MHz, D.sub.2O) 9.98 (br s, 1H) 9.60 (br d, 1H) 8.88 (br d, 1H) 8.37 (s, 2H) 5.03 (br t, 2H) 3.20 (br t, 2H) (Two NH.sub.2 protons missing) A45 (400 MHz, D.sub.2O) 10.07 (s, 1H) 9.83 (d, 1H) 9.07 (dd, 1H) 8.15 (d, 1H) 6.76 (d, 1H) 5.10 (t, 2H) 3.20 (t, 2H) 3.16 (s, 6H) A46 (400 MHz, D.sub.2O) 10.33 (d, 1H) 10.00 (d, 1H) 9.54 (s, 2H) 9.40 (dd, 1H) 5.20 (t, 2H) 3.43 (s, 3H) 3.32 (t, 2H) A47 (400 MHz, D.sub.2O) 10.09 (d, 1H) 9.81 (d, 1H) 9.10 (m, 1H) 7.37 (s, 1H) 5.08 (t, 2H) 3.21 (t, 2H) 2.51 (s, 6H) A48 (400 MHz, D.sub.2O) 10.13 (s, 1H) 9.80 (d, 1H) 9.12 (dd, 1H) 7.27-7.42 (m, 1H) 5.21 (t, 2H) 3.66 (t, 2H) 2.52 (s, 6H) A49 (400 MHz, D.sub.2O) 10.39 (d, 1H) 9.92 (d, 1H) 9.39-9.46 (m, 1H) 9.27 (d, 1H) 8.10 (d, 1H) 5.30 (t, 2H) 3.73 (t, 2H) 2.82 (s, 3H) A50 (400 MHz, D.sub.2O) 10.18 (m, 1H) 9.8 (m, 1H) 9.18 (m, 1H) 8.7 (m, 1H) 7.46 (m, 1H) 5.24 (m, 2H) 3.7 (m, 2H) 2.2 (m, 1H) 1.2 (m, 4H) (one OH proton missing) A51 (400 MHz, D.sub.2O) 10.10 (m, 1H) 9.80 (m, 1H) 9.10 (m, 1H) 8.60 (m, 2H) 5.10 (m, 2H) 3.20 (m, 2H) 1.90 (m, 1H) 1.10 (m, 2H) 0.85 (m, 2H) A52 0 (400 MHz, D.sub.2O) 9.91 (d, 1H) 9.67 (d, 1H) 8.83 (dd, 1H) 8.22 (d, 1H) 7.19 (d, 1H) 4.93 (t, 2H) 2.95 (t, 2H) 2.49 (quin, 2H) A53 (400 MHz, D.sub.2O) 10.05 (d, 1H) 9.84 (d, 1H) 9.11 (dd, 1H) 8.93 (d, 1H) 8.23 (d, 1H) 5.01 (t, 2H) 2.96 (t, 2H) 2.51 (quin, 2H) A54 (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.98 (d, 2H) 7.63 (t, 1H) 5.12 (t, 2H) 3.59 (s, 3H) 3.25 (t, 2H) A55 (400 MHz, CD.sub.3OD) 10.26 (d, 1H) 10.05 (d, 1H) 9.30 (dd, 1H) 9.03 (d, 1H) 8.24 (d, 1H) 5.17 (t, 2H) 3.26 (t, 2H) 2.85 (s, 3H) A56 (400 MHz, CD.sub.3OD) 10.21-10.34 (m, 1H) 9.97 (d, 1H) 9.25-9.35 (m, 1H) 9.10-9.15 (m, 2H) 7.60-7.76 (m, 1H) 7.16-7.34 (m, 5H) 5.16-5.24 (m, 2H) 5.05-5.15 (m, 2H) 3.31-3.39 (m, 2H) A57 (400 MHz, D.sub.2O) 9.94 (d, 1H) 9.81 (d, 1H) 8.97 (dd, 1H) 8.43 (d, 1H) 7.36 (d, 1H) 5.22 (t, 2H) 3.66 (t, 2H) (one NH proton missing) A58 (400 MHz, D.sub.2O) 10.29 (m, 1H) 9.91 (m, 1H) 9.49 (s, 2H) 9.31 (m, 1H) 5.14 (m, 2H) 3.26 (m, 2H) 2.74 (s, 3H) A59 (400 MHz, D.sub.2O) 10.26-10.42 (m, 1H) 9.94 (d, 1H) 9.33-9.49 (m, 1H) 9.23-9.31 (m, 1H) 8.06-8.27 (m, 1H) 8.19 (s, 1H) 5.17 (t, 2H) 3.28 (t, 2H) 3.01 (s, 3H) A60 (400 MHz, CD.sub.3OD) 10.28-10.21 (m, 1H) 9.99 (d, 1H) 9.26 (dd, 1H) 8.93 (d, 1H) 8.04 (d, 1H) 5.27 (t, 2H) 4.16 (s, 3H) 3.59 (t, 2H) A61 (400 MHz, CD.sub.3OD) 10.26-10.22 (m, 1H) 9.87 (d, 1H) 9.49-9.47 (m, 1H) 9.20 (dd, 1H) 8.85-8.82 (m, 1H) 5.24 (t, 2H) 3.58 (t, 2H) 2.71 (s, 3H) A62 0 (400 MHz, CD.sub.3OD) 10.24-10.20 (m, 1H) 9.93 (d, 1H) 9.24 (dd, 1H) 9.02 (d, 1H) 7.89 (d, 1H) 5.11 (t, 2H) 4.11 (s, 3H) 2.93 (t, 2H) 2.61 (quin, 2H) A63 (400 MHz, D.sub.2O) 9.89 (br s, 1H) 9.69 (br d, 1H) 8.82-8.98 (m, 1H) 7.83-8.03 (m, 2H) 7.49 (br d, 1H) 5.02 (br t, 2H) 3.19 (br t, 2H) 2.55 (s, 3H) A64 (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.78 (d, 1H) 8.99 (dd, 1H) 8.82 (d, 1H) 8.29 (d, 1H) 8.13 (t, 1H) 7.70 (dd, 1H) 5.24 (t, 2H) 3.71 (t, 2H) A65 (400 MHz, D.sub.2O) 9.82 (d, 1H) 9.68 (m, 1H) 8.73-8.74 (m, 1H) 8.56-8.57 (m, 1H) 7.91-7.93 (m, 1H) 7.54-7.56 (m, 1H) 5.13 (t, 2H) 3.27 (t, 2H) 2.45 (s, 3H) A66 (400 MHz, D.sub.2O) 9.80 (d, 1H) 9.71 (d, 1H) 8.75 (dd, 1H) 8.52-8.58 (m, 1H) 7.85-7.94 (m, 1H) 7.53 (dd, 1H) 5.21- 5.30 (m, 2H) 3.66-3.75 (m, 2H) 2.44 (s, 3H) A67 (400 MHz, D.sub.2O) 9.91 (d, 1H) 9.72 (d, 1H) 8.91 (dd, 1H) 8.55 (dt, 1H) 7.74-7.82 (m, 1H) 7.61-7.67 (m, 1H) 5.00-5.05 (m, 2H) 3.18 (t, 2H) A68 (400 MHz, D.sub.2O) 10.05-10.10 (d, 1H) 9.80 (d, 1H) 8.02 (m, 1H) 8.60-8.69 (m, 1H) 7.83-7.93 (m, 1H) 7.67-7.79 (m, 1H) 5.15-5.35 (m, 2H) 3.69-3.73 (m, 2H) A69 (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.74 (d, 1H) 8.98 (dd, 1H) 8.80 (d, 1H) 8.25 (d, 1H) 8.11 (dd, 1H) 5.17-5.24 (m, 2H) 3.65-3.72 (m, 2H) A70 (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.77 (d, 1H) 8.99 (dd, 1H) 8.63 (d, 1H) 7.77 (d dd, 1H) 5.19-5.29 (m, 2H) 3.66-3.72 (m, 2H) A71 (400 MHz, D.sub.2O) 9.99 (d, 1H) 9.75 (d, 1H) 8.94 (dd, 1H) 8.70 (d, 1H) 8.34 (dd, 1H) 7.67-7.90 (m, 1H) 5.09 (t, 2H) 3.24 (t, 2H) A72 0 (400 MHz, D.sub.2O) 10.01 (d, 1H) 9.72 (d, 1H) 8.94 (dd, 1H) 8.69 (d, 1H) 8.34 (dd, 1H) 7.74-7.89 (m, 1H) 5.19 (t, 2H) 3.67 (t, 2H) A73 (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.83 (d, 1H) 9.08 (dd, 1H) 8.46 (d, 1H) 8.29 (t, 1H) 8.06 (d, 1H) 5.11 (t, 2H) 3.25 (t, 2H) A74 (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.81 (d, 1H) 9.10 (dd, 1H) 8.48 (d, 1H) 8.28 (t, 1H) 8.06 (d, 1H) 5.24 (t, 2H) 3.7 (t, 2H) A75 (400 MHz, D.sub.2O) 9.91 (d, 1H) 9.67 (d, 1H) 8.87 (dd, 1H) 7.95-8.03 (m, 1H) 7.85-7.94 (m, 1H) 7.48 (d, 1H) 5.14 (t, 2H) 3.61 (t, 2H) 2.54 (s, 3H) A76 (400 MHz, D.sub.2O) 10.21 (s, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 6.41 (s, 1H) 5.14 (t, 2H) 4.04 (s, 6H) 3.28 (t, 2H) A77 (400 MHz, CD.sub.3OD) 10.35-10.47 (m, 1H) 10.05 (d, 1H) 9.37-9.44 (m, 1H) 9.08- 9.15 (m, 2H) 7.65-7.78 (m, 1H) 7.32- 7.43 (m, 2H) 7.18-7.27 (m, 1H) 7.03- 7.15 (m, 2H) 5.30 (t, 2H) 3.58 (t, 2H) A78 (400 MHz, D.sub.2O) 9.98-9.93 (m, 1H) 9.58 (d, 1H) 8.98 (d, 1H) 8.89 (dd, 1H) 8.42 (d, 1H) 4.91 (t, 2H) 4.01 (s, 3H) 2.95 (t, 2H) 2.48 (quin, 2H) A79 (400 MHz, D.sub.2O) 10.06-10.04 (m, 1H) 9.76-9.72 (m, 1H) 9.21 (d, 1H) 9.05 (dd, 1H) 8.88 (d, 1H) 4.97 (t, 2H) 2.96 (t, 2H) 2.51 (quin, 2H) A80 (400 MHz, D.sub.2O) 10.28-10.42 (m, 1H) 9.93-10.10 (m, 1H) 9.37-9.45 (m, 1H) 9.12 (d, 2H) 7.70 (t, 1H) 5.06-5.20 (m, 2H) 3.21 (t, 2H) 1.40-1.46 (m, 9H) A81 (400 MHz, CD.sub.3OD) 10.29-10.43 (m, 1H) 10.02 (d, 1H) 9.36-9.49 (m, 1H) 9.04- 9.18 (m, 2H) 7.63-7.76 (m, 1H) 5.10- 5.24 (m, 2H) 4.92-5.04 (m, 1H) 3.14- 3.41 (m, 2H) 1.12-1.25 (m, 6H) A82 0 (400 MHz, D.sub.2O) 10.07-10.18 (m, 1H) 9.77-9.90 (m, 1H) 9.12-9.23 (m, 1H) 8.96 (d, 2H) 7.52-7.70 (m, 1H) 5.04-5.17 (m, 2H) 4.03 (q, 2 H) 3.14-3.30 (m, 2H) 1.01-1.13 (m, 3H) A83 (400 MHz, D.sub.2O) 10.09-10.03 (m, 1H) 9.80-9.76 (m, 1H) 9.15 (s, 1H) 9.04 (dd, 1H) 8.66 (s, 1H) 5.20 (t, 2H) 3.65 (t, 2H) 2.62 (s, 3H) A84 (400 MHz, D.sub.2O) 10.08-10.04 (m, 1H) 9.78 (d, 1H) 9.32 (s, 1H) 9.08 (dd, 1H) 8.82 (s, 1H) 4.99 (t, 2H) 2.96 (t, 2H) 2.57-2.46 (m, 2H) A85 (400 MHz, CD.sub.3OD) 10.29-10.24 (m, 1H) 10.02-9.95 (m, 1H) 9.41 (s, 1H) 9.29- 9.25 (m, 1H) 8.79 (s, 1H) 5.16 (t, 2H) 3.30-3.23 (m, 2H) 2.73 (s, 3H) (one CO.sub.2H proton missing) A86 (400 MHz, CD.sub.3OD) 10.16-10.12 (m, 1H) 10.09 (d, 1H) 9.22 (dd, 1H) 8.36 (d, 1H) 7.44 (d, 1H) 5.18 (t, 2H) 3.27 (t, 2H) (one CO.sub.2H proton and one OH proton missing) A87 (400 MHz, D.sub.2O) 9.83-9.86 (m, 1H) 9.62- 9.75 (m, 1H) 9.01-9.04 (m, 2H) 7.40- 7.83 (m, 1H) 5.18-5.25 (m, 2H) 3.57- 3.80 (m, 2H) 2.64-2.87 (m, 3H) A88 (400 MHz, D.sub.2O) 9.76 (d, 1H) 9.69-9.88 (m, 1H) 9.02 (d, 1H) 8.77 (d, 1H) 7.69 (t, 1H) 5.21 (t, 2H) 3.71 (t, 2H) 2.94 (s, 3H) A89 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.93 (d, 1H) 9.25 (dd, 1H) 9.05 (d, 2H) 7.70 (t, 1H) 5.22 (t, 2H) 3.30-3.40 (m, 2H) 3.27 (s, 3H) (one NH proton missing) A90 (400 MHz, D.sub.2O) 10.10-10.04 (m, 1H) 9.67 (d, 1H) 9.05 (dd, 1H) 8.91 (s, 1H) 8.34 (s, 1H) 4.94 (t, 2H) 4.01 (s, 3H) 2.97-2.90 (m, 2H) 2.54-2.44 (m, 2H) A91 (400 MHz, D.sub.2O) 9.98 (m, 1H) 9.78 (m, 1H) 8.98 (m, 1H) 8.76 (s, 1H) 8.24 (m, 1H) 8.10 (m, 1H) 7.68 (m, 1H) 5.12 (m, 2H) 4.10 (m, 2H) 3.26 (m, 2H) 1.14 (m, 3H) A92 0 (400 MHz, D.sub.2O) 10.23 (m, 1H) 9.89 (m, 1H) 9.25 (m, 1H) 9.12 (s, 2H) 5.16 (m, 2H) 3.26 (m, 2H) 3.08 (s, 3H) 3.02 (s, 3H) A93 (400 MHz, D.sub.2O) 10.27 (m, 1H) 9.94 (m, 1H) 9.33 (s, 3H) 5.18 (m, 2H) 3.26 (m, 2H) 2.94 (m, 3H) (one NH proton missing) A94 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.84 (d, 1H) 9.21 (d, 1H) 6.91 (s, 1H) 5.25 (t, 2H) 4.05 (s, 3H) 3.70 (t, 2H) 2.52 (s, 3H) A95 (400 MHz, D.sub.2O) 9.89-9.98 (m, 1H) 9.83 (d, 1H) 8.97 (dd, 1H) 6.49 (s, 1H) 5.18 (t, 2H) 3.60 (t, 2H) 2.33 (s, 3H) (one NH proton missing) A96 (400 MHz, D.sub.2O) 10.06 (d, 1H) 9.65-9.77 (m, 1H) 9.00-9.09 (m, 1H) 8.48-8.63 (m, 1H) 5.02 (t, 2H) 3.15 (t, 2H) 2.49 (s, 3H) 2.26 (s, 3H) A97 (400 MHz, D.sub.2O) 10.10 (d, 1H) 9.73 (d, 1H) 9.07 (dd, 1H) 8.57 (s, 1H) 5.13-5.18 (m, 2H) 3.58-3.64 (m, 2H) 2.49 (s, 3H) 2.26 (s, 3H) A98 (400 MHz, D.sub.2O) 10.06-10.03 (m, 1H) 9.75-9.71 (m, 1H) 9.12-9.09 (m, 1H) 9.04 (dd, 1H) 8.74 (dd, 1H) 4.97 (t, 2H) 3.00-2.94 (m, 2H) 2.56-2.47 (m, 2H) A99 (400 MHz, D.sub.2O) 10.23 (d, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 8.89 (s, 1H) 5.25 (m, 2H) 3.70 (m, 2H) 2.70 (s, 3H) A100 (400 MHz, D.sub.2O) 10.53 (br s, 1H) 9.58 (br s, 1H) 9.16 (br s, 1H) 8.85-8.92 (m, 1H) 5.15-5.22 (m, 2H) 3.23 (br s, 2H) 2.69 (s, 3H) A101 (400 MHz, D.sub.2O) 10.20 (d, 1H) 9.85 (d, 1H) 9.21 (dd, 1H) 8.66 (d, 1H) 7.05 (d, 1H) 5.13 (t, 2H) 4.08 (s, 3H) 3.26 (t, 2H) A102 0 (400 MHz, D.sub.2O) 9.65-9.81 (m, 2H) 8.67- 8.77 (m, 1H) 8.53-8.61 (m, 1H) 7.91- 8.00 (m, 1H) 4.95-5.10 (m, 2H) 2.98- 3.02 (m, 2H) 2.54-2.56 (m, 2H) 2.43- 2.45 (m, 3H) A103 (400 MHz, D.sub.2O) 9.77 (d, 1H) 9.68 (s, 1H) 8.72 (d, 1H) 8.54 (s, 1H) 7.92 (s, 1H) 5.22 (t, 2H) 3.67 (t, 2H) 2.42 (s, 3H) A104 (400 MHz, D.sub.2O) 9.77-9.85 (m, 1H) 9.72 (br s, 1H) 8.74 (br s, 1H) 8.52-8.59 (m, 1H) 7.73 (br s, 1H) 5.26 (br s, 2H) 3.71 (br s, 2H) 2.49 (br s, 3H) A105 (400 MHz, D.sub.2O) 10.19 (d, 1H) 9.83 (d, 1H) 9.19 (dd, 1H) 6.92 (s, 1H) 5.11 (s, 2H) 4.05 (s, 3H) 3.22 (t, 2H) 2.52 (s, 3H) A106 (400 MHz, D.sub.2O) 10.40-10.51 (m, 1H) 9.48-9.65 (m, 1H) 8.99-9.23 (m, 1H) 8.36-8.54 (m, 1H) 5.13-5.30 (m, 2H) 3.97-4.21 (m, 3H) 3.17-3.37 (m, 2H) 2.14-2.25 (m, 3H) A107 (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.86 (d, 1H) 9.21-9.15 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) A108 (400 MHz, D.sub.2O) 10.21-10.16 (m, 1H) 9.92 (d, 1H) 9.25-9.20 (m, 2H) 8.51 (d, 1H) 5.26 (t, 2H) 3.68 (t, 2H) A109 (400 MHz, D.sub.2O) 10.20-10.14 (m, 1H) 9.93 (d, 1H) 9.56-9.53 (m, 1H) 9.21 (dd, 1H) 8.79-8.74 (m, 1H) 5.25 (t, 2H) 3.67 (t, 2H) A110 (400 MHz, D.sub.2O) 10.19-10.16 (m, 1H) 9.87 (d, 1H) 9.65 (s, 1H) 9.22 (s, 1H) 9.19 (dd, 1H) 5.23 (t, 2H) 3.66 (t, 2H) A111 (400 MHz, D.sub.2O) 10.08-10.04 (m, 1H), 9.84-9.79 (m, 1H) 9.06 (dd, 1H) 9.01 (d, 1H) 7.95 (d, 1H) 5.01 (t, 2H) 4.01 (s, 3H) 3.01-2.95 (m, 2H) 2.58-2.49 (m, 2H) A112 0 (400 MHz, D.sub.2O) 10.18-10.15 (m, 1H) 9.90-9.85 (m, 1H) 9.56-9.53 (m, 1H) 9.30-9.27 (m, 1H) 9.19 (dd, 1H) 5.23 (t, 2H) 3.67 (t, 2H) A113 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.86 (d, 1H) 9.23 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 5.06 (dt, 2H) 3.85 (quin, 2H) 2.44- 2.53 (m, 2H) 1.13 (t, 3H) (one OH proton missing) A114 (400 MHz, D.sub.2O) 10.17-10.12 (m, 1H) 9.75-9.71 (m, 1H) 9.15 (dd, 1H) 8.97 (d, 2H) 7.61 (t, 1H) 5.04 (s, 2H) 1.37 (s, 6H) A115 (400 MHz, D.sub.2O) 10.00-10.13 (m, 1H) 9.67-9.78 (m, 1H) 8.93-9.06 (m, 1H) 8.30-8.44 (m, 1H) 7.40 (d, 1H) 4.98 (t, 2H) 4.11 (s, 3H) 2.97 (t, 2H) 2.52 (quin, 2H) A116 (400 MHz, D.sub.2O) 9.86-9.98 (m, 1H) 9.72- 9.81 (m, 1H) 8.96 (dd, 1H) 8.34-8.48 (m, 1H) 7.35 (d, 1H) 4.86-5.10 (m, 2H) 2.84- 3.05 (m, 2H) 2.43 (s, 2H) (one NH proton missing) A117 (400 MHz, D.sub.2O) 9.98-10.10 (m, 1H) 9.85 (d, 1H) 9.13-9.22 (m, 1H) 9.06 (dd, 1H) 8.12-8.24 (m, 1H) 5.16-5.31 (m, 2H) 3.58-3.73 (m, 2H) 2.57-2.69 (m, 3H) A118 (400 MHz, CD.sub.3OD) 10.28 (d, 1H) 10.14 (d, 1H) 9.40-9.32 (m, 2H) 8.67 (d, 1H) 5.21 (t, 2H) 3.34-3.26 (m, 2H) (one CO.sub.2H proton missing) A119 (400 MHz, CD.sub.3OD) 10.39-10.33 (m, 1H) 10.14 (d, 1H) 9.71-9.68 (m, 1H) 9.44 (dd, 1H) 8.93 (d, 1H) 5.20 (t, 2H) 3.35- 3.24 (m, 2H) (one CO.sub.2H proton missing) A120 400 MHz, CD.sub.3OD) 10.31-10.23 (m, 1H) 10.08 (d, 1H) 9.89 (s, 1H) 9.38-9.31 (m, 2H) 5.19 (t, 2H) 3.34-3.26 (m, 2H) (one CO.sub.2H proton missing) A121 (400 MHz, CD.sub.3OD) 10.35-10.28 (m, 1H) 10.09 (d, 1H) 9.77 (d, 1H) 9.40-9.34 (m, 2H) 5.19 (t, 2H) 3.34-3.23 (m, 2H) (one CO.sub.2H proton missing) A122 00 (400 MHz, D.sub.2O) 10.24-10.20 (m, 1H) 9.91 (d, 1H) 9.20 (dd, 1H) 8.76 (d, 1H) 8.40 (d, 1H) 5.26 (t, 2H) 3.68 (t, 2H) A123 01 (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.79 (d, 1H) 9.20 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.04 (s, 2H) 1.25 (s, 6H) (one CO.sub.2H proton missing) A124 02 (400 MHz, D.sub.2O) 10.26 (d, 1H) 9.89 (d, 1H) 9.27 (dd, 1H) 9.00-9.06 (m, 2H) 7.69 (t, 1H) 5.11-5.23 (m, 2H) 4.03-4.15 (m, 4H) 2.84 (dt, 2H) 1.21 (t, 6H) A125 03 (400 MHz, D.sub.2O) 10.18-10.13 (m, 1H) 9.87-9.82 (m, 1H) 9.20-9.14 (m, 1H) 8.98 (d, 2H) 7.63 (s, 1H) 5.10 (s, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) A126 04 (400 MHz, CD.sub.3OD) 10.39 (d, 1H) 10.15 (d, 1H) 9.40 (dd, 1H) 8.89 (d, 1H) 8.45 (d, 1H) 5.22 (t, 2H) 3.34-3.25 (m, 2H) (one CO.sub.2H proton missing) A127 05 (400 MHz, D.sub.2O) 9.99 (d, 1H) 9.91 (d, 1H) 9.04 (d, 1H) 8.34 (d, 1H) 6.74 (d, 1H) 5.13 (t, 2H) 3.24 (t, 2H) (One NH proton and one CO.sub.2H proton missing) A128 06 (400 MHz, D.sub.2O) 9.99 (s, 1H) 9.62 (d, 1H) 8.88 (d, 1H) 8.71 (dd, 1H) 8.37 (d, 1H) 7.79 (dd, 1H) 5.14 (t, 2H) 3.25 (t, 2H) (one CO.sub.2H proton missing) A129 07 (400 MHz, D.sub.2O) 10.29 (d, 1H) 9.95- 10.00 (m, 1H) 9.32-9.41 (m, 3H) 5.18 (t, 2H) 3.25-3.35 (m, 2H) (one CO.sub.2H proton missing) A130 08 (400 MHz, D.sub.2O) 10.16-10.25 (m, 1H) 9.81-9.89 (m, 1H) 9.19-9.27 (m, 1H) 8.97-9.09 (m, 2H) 7.63-7.74 (m, 1H) 5.08-5.20 (m, 1H) 4.92-5.01 (m, 1H) 3.35-3.47 (m, 1H) 1.31 (d, 3H) (one CO.sub.2H proton missing) A131 09 (400 MHz, D.sub.2O) 10.18 (m, 1H) 9.97 (m, 1H) 9.21 (m, 1H) 8.98 (m, 2H) 7.61 (m, 1H) 3.36 (s, 2H) 1.94 (s, 6H) (one CO.sub.2H proton missing) A132 0 (400 MHz, D.sub.2O) 9.72 (d, 1H) 8.98 (d, 1H) 8.66-8.74 (m, 1H) 8.71 (d, 1H) 7.65 (t, 1H) 5.06 (t, 2H) 3.21 (t, 2H) 2.87 (s, 3H) (one CO.sub.2H proton missing) A133 (400 MHz, D.sub.2O) 9.72 (d, 1H) 8.98 (d, 1H) 8.66-8.74 (m, 1H) 8.71 (d, 1H) 7.65 (t, 1H) 5.06 (t, 2H) 3.21 (t, 2H) 2.87 (s, 3H) (one CO.sub.2H proton missing) A134 (400 MHz, D.sub.2O) 10.20-10.18 (m, 1H) 9.81 (dd, 1H) 9.19 (dd, 1H) 9.00 (d, 2H), 7.65 (t, 1H) 5.10-5.07 (m, 2H) 3.84-3.74 (m, 1H) 1.39 (d, 3H) A135 (400 MHz, D.sub.2O) 10.00 (d, 1H) 9.73 (d, 1H) 8.96 (d, 1H) 8.50 (s, 1H) 7.69 (d, 1H) 5.18-5.23 (m, 2H) 3.66-3.71 (m, 2H) 2.45 (s, 3H) A136 (400 MHz, D.sub.2O) 9.85 (s, 1H) 9.80 (d, 1H) 8.95 (dd, 1H) 8.52 (s, 1H) 7.95 (s, 1H) 5.24 (t, 2H) 3.67-3.72 (m, 2H) 2.40 (s, A137 (400 MHz, D.sub.2O) 9.78-9.89 (m, 1H) 8.96 (dd, 1H) 8.87-9.00 (m, 1H) 8.53 (d, 1H) 7.96 (d, 1H) 5.14 (t, 2H) 3.28 (t, 2H) 2.41 (s, 3H) (one CO.sub.2H proton missing) A138 (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.87 (d, 1H) 9.32 (dd, 1H) 9.12-9.08 (m, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.12 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) A139 (400 MHz, D.sub.2O) 10.05-10.15 (m, 1H) 9.84-9.94 (m, 1H) 9.28-9.39 (m, 1H) 9.05-9.14 (m, 1H) 8.41-8.56 (m, 1H) 7.90-8.06 (m, 1H) 5.07-5.21 (m, 2H) 3.56-3.67 (m, 3H) 3.22-3.34 (m, 2H) A140 (400 MHz, D.sub.2O) 9.86 (d, 1H) 9.62 (d, 1H) 8.85 (d, 1H) 8.70 (m, 1H) 8.35 (d, 1H) 7.77 (m, 1H) 5.24 (m, 2H) 3.65 (m, 2H) A141 (400 MHz, D.sub.2O) 9.83-9.92 (m, 2H) 8.98 (d, 1H) 8.68 (d, 1H) 8.12 (d, 1H) 7.59- 7.66 (m, 1H) 5.27 (t, 2H) 3.71 (t, 2H) A142 0 (400 MHz, D.sub.2O) 9.87 (d, 1H) 9.83 (d, 1H) 8.99 (dd, 1H) 8.71 (d, 1H) 8.23 (d, 1H) 5.25 (t, 2H) 3.70 (t, 2H) A143 (400 MHz, D.sub.2O) 10.24 (d, 1H) 9.80 (d, 1H) 9.25 (dd, 1H) 9.04 (d, 2H) 7.68 (t, 1H) 5.21 (dd, 1H) 4.93 (dd, 1H) 4.64- 4.71 (m, 1H) 3.19-3.36 (m, 2H) (one OH proton missing) A144 (400 MHz, D.sub.2O) 9.95 (d, 1H) 9.74 (d, 1H) 8.93 (dd, 1H) 8.58 (d, 1H) 7.67-7.83 (m, 1H) 5.06 (t, 2H) 3.26 (t, 2H) (one CO.sub.2H proton missing) A145 (400 MHz, D.sub.2O) 9.68 (d, 1H) 8.73 (d, 1H) 8.49 (d, 1H) 8.09 (td, 1H) 7.80 (d, 1H) 7.65 (dd, 1H) 5.07 (t, 2H) 3.26 (t, 2H) 2.77 (s, 3H) (one CO.sub.2H proton missing) A146 (400 MHz, D.sub.2O) 10.23-10.33 (d, 1H) 9.81 (d, 1H) 9.30 (dd, 1H) 9.15 (d, 1H) 8.06 (d, 1H) 5.01 (t, 2H) 2.97 (t, 2H) 2.52 (m, 2H) (one CO.sub.2H proton missing) A147 (400 MHz, D.sub.2O) 10.23 (d, 1H) 9.85 (d, 1H) 9.25 (m, 2H) 8.06 (d, 1H) 5.02 (t, 2H) 2.98 (t, 2H) 2.53 (t, 2H) A148 (400 MHz, D.sub.2O) 9.99 (s, 1H) 9.77 (d, 1H) 8.96 (dd, 1H) 8.80 (d, 1H) 8.25 (d, 1H) 8.06-8.12 (m, 1H) 7.68 (t, 1H) 5.10 (t, 2H) 3.25 (t, 2H) (one CO.sub.2H proton missing) A149 (400 MHz, D.sub.2O) 9.78-9.88 (m, 2H) 8.95 (dd, 1H) 8.66 (d, 1H) 8.10 (d, 1H) 7.56- 7.65 (m, 1H) 5.12 (t, 2H) 3.23 (t, 2H) (one CO.sub.2H proton missing) A150 (400 MHz, D.sub.2O) 9.99 (d, 1H) 9.75 (d, 1H) 8.96 (dd, 1H) 8.80 (d, 1H) 8.24 (d, 1H) 8.10 (dd, 1H) 5.09 (t, 2H) 3.25 (t, 2H) (one CO.sub.2H proton missing) A151 (400 MHz, D.sub.2O) 9.80 (d, 1H) 9.68 (s, 1H) 8.72 (d, 1H) 8.46-8.54 (m, 1H) 7.71 (d, 1H) 5.12 (t, 2H) 3.26 (t, 2H) 2.48 (s, 3H) (one CO.sub.2H proton missing) A152 0 (400 MHz, D.sub.2O) 9.75 (d, 1H) 9.69 (d, 1H) 8.70 (dd, 1H) 8.42 (s, 1H) 7.74 (s, 1H) 5.23 (t, 2H) 3.69 (t, 2H) 2.42 (s, 3H) 2.36 (s, 3H) A153 (400 MHz, D.sub.2O) 9.84 (s, 1H) 9.64-9.69 (m, 1H) 8.99-9.05 (m, 1H) 9.02 (d, 1H) 7.67 (t, 1H) 5.09 (t, 2H) 3.26 (t, 2H) 2.78 (s, 3H) A154 (400 MHz, D.sub.2O) 10.25 (s, 1H) 9.84 (d, 1H) 9.26 (d, 1H) 8.97 (d, 1H) 7.72 (d, 1H) 5.05 (t, 2H) 4.86 (s, 2H) 3.02 (t, 2H) 2.59 (t, 2H) (one OH proton missing) A155 (400 MHz, D.sub.2O) 9.96 (d, 1H) 9.69 (d, 1H) 8.90 (dd, 1H) 8.62 (s, 1H) 8.14 (d, 1H) 7.89 (dd, 1H) 5.19 (t, 2H) 3.67 (t, 2H) 2.40 (s, 3H) A156 (400 MHz, D.sub.2O) 9.81 (d, 1H) 9.68 (d, 1H) 8.73 (dd, 1H) 8.57 (d, 1H) 7.95 (d, 1H) 5.12 (t, 2H) 3.26 (t, 2H) 2.44 (s, 3H) (one CO.sub.2H proton missing) A157 (400 MHz, D.sub.2O) 9.86 (d, 1H) 9.81 (d, 1H) 8.90 (dd, 1H) 8.73 (d, 1H) 8.63 (d, 1H) 7.89 (t, 1H) 5.16 (br t, 2H) 3.29 ppm (t, 2H) (one CO.sub.2H proton missing) A158 (400 MHz, D.sub.2O) 10.04-9.99 (m, 1H) 9.87 (d, 1H) 9.07 (dd, 1H) 8.51 (d, 1H) 7.57 (d, 1H) 5.23 (t, 2H) 3.66 (t, 2H) (two NH protons missing) A159 (400 MHz, D.sub.2O) 9.90 (d, 1H) 9.85 (d, 1H) 8.93 (dd, 1H) 8.79 (d, 1H) 8.67 (d, 1H) 8.01 (t, 1H) 5.12-5.35 (m, 2H) 3.63- 3.81 (m, 2H) (one SO.sub.3H proton missing) A160 (400 MHz, CD.sub.3OD) 10.16 (d, 1H) 10.00 (d, 1H) 9.18 (dd, 1H) 8.57 (d, 1H) 7.53 (d, 1H) 5.12 (t, 2H) 3.25 (t, 2H) (two NH.sub.2 protons and one CO.sub.2H proton missing) A161 (400 MHz, D.sub.2O) 9.95 (s, 1H) 9.87 (d, 1H) 9.00 (dd, 1H) 8.44 (s, 1H) 5.09 (t, 2H) 3.22 (t, 2H) (one CO.sub.2H proton missing) A162 0 (400 MHz, D.sub.2O) 10.21 (s, 1H) 9.87 (d, 1H) 9.23 (dd, 1H) 9.02 (s, 2H) 5.16 (t, 2H) 4.81 (s, 2H) 3.26 (t, 2H) (one OH proton and one CO.sub.2H proton missing) A163 (400 MHz, CD.sub.3OD) 10.12-10.06 (m, 1H) 10.01-9.93 (m, 1H) 9.10 (dd, 1H) 8.63 (d, 1H) 7.43 (d, 1H) 5.14 (t, 2H) 3.26 (t, 2H) (two NH.sub.2 protons and one CO.sub.2H proton missing) A164 (400 MHz, D.sub.2O) 9.92-9.86 (m, 1H) 9.82- 9.76 (m, 1H) 8.90 (dd, 1H) 8.58-8.49 (m, 1H) 7.32 (d, 1H) 5.23-5.18 (m, 2H) 3.67- 3.63 (m, 2H) (two NH.sub.2 protons missing) A165 (400 MHz, D.sub.2O) 9.82-10.02 (m, 2H) 8.86-9.05 (m, 2H) 8.44 (s, 1H) 8.22 (dd, 1H) 5.24-5.34 (m, 2H) 3.66-3.77 ppm (m, 2H) A166 (400 MHz, D.sub.2O) 9.78-9.94 (m, 2H) 8.84- 9.04 (m, 2H) 8.43 (s, 1H) 8.21 (dd, 1H) 5.15 (t, 2H) 3.28 (t, 2H) (one CO.sub.2H proton missing) A167 (400 MHz, D.sub.2O) 10.03-10.10 (m, 1H) 9.83-9.89 (m, 1H) 9.38 (s, 1H) 9.15 (dd, 1H) 9.07 (d, 1H) 8.31 (dd, 1H) 5.08 (s, 2H) 1.28 (s, 6H) (one CO.sub.2H proton missing) A168 (400 MHz, D.sub.2O) 10.23 (d, 1H) 9.86 (d, 1H) 9.20 (dd, 1H) 8.82 (d, 1H) 8.70 (d, 2H) 8.03 (d, 1H) 5.04 (t, 2H) 3.00 (t, 2H) 2.56 (quin, 2H) A169 (400 MHz, D.sub.2O) 10.1 (d, 1H) 9.85 (d, 1H) 9.14-9.13 (m, 1H) 9.09 (dd, 1H) 8.47-8.41 (m, 2H) 5.25 (t, 2H) 3.70 (t, 2H) A170 (400 MHz, D.sub.2O) 10.24 (d, 1H) 9.87 (d, 1H) 9.24 (m, 1H) 9.02 (s, 2H) 5.26 (m, 2H) 4.80 (s, 2H) 3.70 (m, 2H) (one OH proton missing) A171 (400 MHz, D.sub.2O) 10.07 (d, 1H) 9.88 (d, 1H) 9.37 (s, 1H) 9.13 (dd, 1H) 9.03- 9.08 (m, 1H) 8.26-8.33 (m, 1H) 5.14 (dd, 1H) 4.98 (dd, 1H) 3.41-3.45 (m, 1H) 1.30 (d, 3H) (one CO.sub.2H proton missing) A172 0 (400 MHz, D.sub.2O) 10.12 (d, 1H) 9.95 (d, 1H) 9.39 (d, 1H) 9.06-9.16 (m, 2H) 8.31 (dd, 1H) 5.50-5.60 (m, 1H) 3.37 (dd, 1H) 3.14 (dd, 1H) 1.72 (d, 3H) (one CO.sub.2H proton missing) A173 (400 MHz, D.sub.2O) 10.24 (m, 1H) 9.80 (m, 1H) 9.04 (m, 1H) 8.44 (s, 1H) 5.03 (m, 2H) 3.04 (m, 2H) 2.50 (m, 2H) (one NH proton missing) A174 (400 MHz, D.sub.2O) 10.10 (d, 1H) 9.84 (d, 1H) 9.13 (s, 1H) 9.08 (dd, 1H) 8.45- 8.39 (m, 2H) 5.25 (t, 2H) 3.71 (t, 2H) A175 (400 MHz, D.sub.2O) 9.91-9.89 (m, 2H) 9.04-9.02 (m, 2H) 8.51 (s, 1H) 5.27 (t, 2H) 3.71 (t, 2H) A176 (400 MHz, D.sub.2O) 10.07 (d, 1H) 9.86 (d, 1H) 9.14-9.13 (m, 1H) 9.08 (dd, 1H) 8.47-8.40 (m, 2H) 5.13 (t, 2H) 3.25 (t, 2H) (one CO.sub.2H proton missing) A177 (400 MHz, D.sub.2O) 9.77 (d, 1H) 9.65 (d, 1H) 8.69 (dd, 1H) 8.42 (s, 1H) 7.76 (s, 1H) 5.10 (t, 2H) 3.24 (t, 2H) 2.41 (s, 3H) 2.36 ppm (s, 3H) (one CO.sub.2H proton missing) A178 (400 MHz, D.sub.2O) 9.95 (s, 1H) 9.74 (d, 1H) 8.93 (dd, 1H) 8.48 (s, 1H) 7.70 (s, 1H) 5.07 (t, 2H) 3.22 (m, 2H) 2.44 (s, 3H) (one CO.sub.2H proton missing) A179 (400 MHz, D.sub.2O) 10.36 (d, 1H) 9.66 (d, 1H) 9.29 (d, 1H) 8.97 (dd, 1H) 8.92 (dd, 1H) 8.85 (m, 1H) 8.12 (m, 1H) 5.36 (t, 2H) 3.76 (t, 2H) A180 (400 MHz, D.sub.2O) 10.25 (d, 1H) 9.83 (dd, 1H) 9.28 (dd, 1H) 9.06 (m, 2H) 7.73 (dd, 1H) 5.33 (dd, 1H) 5.23 (dd, 1H) 4.98 (m, 1H) (one OH proton and one CO.sub.2H proton missing) A181 (400 MHz, CD.sub.3OD) 10.43-10.37 (m, 1H) 9.93 (dd, 1H) 9.34 (dd, 1H) 9.11 (d, 2H) 7.68 (t, 1H) 5.66-5.53 (m, 1H) 3.66 (dd, 1H) 3.43 (dd, 1H) 1.83 (d, 3H) A182 0 (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.32 (dd, 1H) 9.10 (dd, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.13 (t, 2H) 3.26 (t, 2H) (one CO.sub.2H proton missing) A183 (400 MHz, D.sub.2O) 9.83 (d, 1H) 9.54 (d, 1H) 8.92 (d, 1H) 8.81 (dd, 1H) 8.17- 8.23 (m, 1H) 8.10-8.16 (m, 1H) 4.79- 4.81 (m, 2H) 2.78 (t, 2H) 2.33 (q, 2H) (two NH protons missing) A184 (400 MHz, CD.sub.3OD) 10.41-10.35 (m, 1H) 10.05-9.99 (m, 1H) 9.31 (dd, 1H) 9.12 (d, 2H) 7.67 (t, 1H) 3.67 (s, 2H) 2.10 (s, 6H) A185 (400 MHz, D.sub.2O) 10.22-10.14 (m, 1H) 9.85-9.77 (m, 1H) 9.24-9.16 (m, 1H) 9.04-8.95 (m, 2H) 7.70-7.60 (m, 1H) 5.13-4.96 (m, 2H) 3.05-2.91 (m, 1H) 2.66-2.51 (m, 1H) 2.42-2.25 (m, 1H) 1.36-1.26 (m, 3H) A186 (400 MHz, D.sub.2O) 10.25 (s, 1H) 9.82 (d, 1H) 9.30 (dd, 1H) 9.27 (d, 1H) 8.08 (d, 1H) 4.98 (t, 2H) 4.15 (t, 2H) (one OH proton missing) A187   (400 MHz, CD.sub.3OD) 10.01 (d, 1H) 9.94 (d, 1H) 9.00-8.95 (m, 1H) 6.87 (s, 1H) 5.39-5.25 (m, 2H) 3.30-3.22 (m, 2H) (Four NH protons missing) [isolated as a 1:1 mixture of isomers with 10.36 (s, 1H) 9.71 (d, 1H) 8.95-8.90 (m, 1H) 6.82 (s, 1H), 5.39-5.25 (m, 2H) 3.30-3.22 (m, 2H) (Four NH protons missing)] A188 (400 MHz, CD.sub.3OD) 10.00-9.98 (m, 1H) 9.96 (d, 1H) 9.01 (dd, 1H) 6.78 (s, 1H) 5.13 (t, 2H) 3.29-3.23 (m, 2H) (Four NH protons and one CO.sub.2H proton missing) A189 (400 MHz, D.sub.2O) 10.13 (d, 1H) 10.03 (d, 1H) 9.42 (d, 1H) 9.17 (dd, 1H) 9.10 (d, 1H) 8.35 (dd, 1H) 3.39 (s, 2H) 1.96 (s, 6H) (one CO.sub.2H proton missing) A190 (400 MHz, D.sub.2O) 10.12 (d, 1H) 9.83 (d, 1H) 9.41 (s, 1H) 9.19 (dd, 1H) 9.10 (br s, 1H) 8.34 (dd, 1H) 5.30 (dd, 1H) 5.18 (dd, 1H) 4.86 (dd, 1H) (one OH proton and one CO.sub.2H proton missing) A191 0 (400 MHz, D.sub.2O) 10.21 (d, 1H) 9.94 (d, 1H) 9.61 (d, 1H) 9.31 (d, 1H) 9.24 (dd, 1H) 5.30 (t, 2H) 3.73 (t, 2H) A192 (400 MHz, CD.sub.3OD) 10.47-10.41 (m, 1H) 10.07-10.00 (m, 1H) 9.49 (dd, 1H) 9.13 (d, 2H) 7.71 (t, 1H) 6.14 (q, 1H) 3.84 (s, 3H) 2.07 (d, 3H) A193 (400 MHz, CD.sub.3OD) 10.50-10.40 (m, 1H) 10.07-9.98 (m, 1H) 9.51 (dd, 1H) 9.15 (d, 2H) 7.70 (t, 1H) 6.02 (q, 1H) 2.02 (d, 3H) 1.48 (s, 9H) A194 (400 MHz, D.sub.2O) 10.28 (d, 1H) 9.87 (d, 1H) 9.29 (dd, 1H) 9.07 (d, 2H) 7.72 (t, 1H) 5.18-5.28 (m, 2H) 4.62-4.72 (m, 2H) A195 (400 MHz, D.sub.2O) 10.25 (d, 1H) 9.81 (d, 1H) 9.26 (dd, 1H) 9.05 (d, 2H) 7.70 (t, 1H) 4.94-5.08 (m, 2H) 4.17-4.22 (m, 2H) (one OH proton missing) A196 (400 MHz, D.sub.2O) 9.75 (m, 1H) 9.70 (m, 1H) 8.75 (m, 1H) 8.49 (m, 1H) 7.72 (m, 1H) 5.04 (m, 2H) 3.03 (m, 2H) 2.57 (m, 2H) 2.48 (m, 3H) A197 (400 MHz, D.sub.2O) 9.92 (d, 1H) 9.89 (d, 1H) 9.04 (td, 2H) 8.54 (d, 1H) 5.16 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) A198 (400 MHz, D.sub.2O) 10.21 (d, 1H) 9.81- 9.89 (m, 1H) 9.18-9.26 (m, 1H) 9.02 (d, 2H) 7.67 (t, 1H) 5.09 (dt, 2H) 2.46-2.60 (m, 2H) (two POH protons missing) A199 (400 MHz, D.sub.2O) 9.95 (d, 1H) 9.72 (d, 1H) 8.91 (dd, 1H) 8.65 (d, 1H) 8.16 (d, 1H) 7.98-7.87 (m, 1H) 5.08 (t, 2H) 3.26 (t, 2H) 2.42 (s, 3H) (one CO.sub.2H proton missing) A200 (400 MHz, D.sub.2O) 10.07 (d, 1H) 9.86 (d, 1H) 9.13 (s, 1H) 9.07 (dd, 1H) 8.44- 8.38 (m, 2H) 5.14 (t, 2H) 3.28 (t, 2H) (one CO.sub.2H proton missing) A201 0 (400 MHz, D.sub.2O) 10.26 (d, 1H) 9.90 (d, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 5.17 (t, 2H) 4.09 (dd, 1H) 2.76-2.79 (m, 2H) (Three NH protons and one CO.sub.2H proton missing) A202 (400 MHz, D.sub.2O) 10.18 (d, 1H) 9.92 (d, 1H) 9.51 (d, 1H) 9.43 (d, 1H) 9.20 (dd, 1H) 5.18 (t, 2H) 3.31 (t, 2H) (two NH protons and one CO.sub.2H proton missing) A203 (400 MHz, D.sub.2O) 9.84-9.78 (m, 2H) 8.87 (dd, 1H) 8.80-8.75 (m, 2H) 8.02-7.96 (m, 2H) 5.10 (t, 2H) 3.61 (s, 3H) 3.26 (t, 2H) A204 (400 MHz, D.sub.2O) 10.23 (d, 1H) 9.83 (d, 1H) 9.24 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 4.97 (t, 2H) 4.05-4.15 (m, 4H) 2.35- 2.48 (m, 2H) 1.93-2.09 (m, 2H) 1.27 (t, 6H) A205 (400 MHz, D.sub.2O) 10.16-10.13 (m, 1H) 9.72-9.68 (m, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (d, 2H) (one OH proton missing) A206 (400 MHz, D.sub.2O) 10.21 (d, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 5.00 (t, 2H) 3.70 (t, 2H) 2.31-2.39 (m, 2H) (one OH proton missing) A207 (400 MHz, D.sub.2O) 10.22 (s, 1H) 9.87 (d, 1H) 9.24 (d, 1H) 8.99-9.04 (m, 2H) 7.66 (t, 1H) 5.16 (t, 2H) 4.17 (dd, 1H) 2.69- 2.85 (m, 2H) (Three NH protons and one CO.sub.2H proton missing) A208 (400 MHz, D.sub.2O) 10.26 (s, 1H) 9.94 (d, 1H) 9.31-9.34 (m, 1H) 9.04 (dd, 2H) 7.69 (t, 1H) 5.48 (d, 2H) 4.75 (t, 1H) (Three NH protons and one CO.sub.2H proton missing) A209 (400 MHz, D.sub.2O) 10.34 (s, 1H) 9.99 (d, 1H) 9.46 (s, 2H) 9.39 (m, 1H) 5.21 (t, 2H) 3.28 (t, 2H) 2.72 (s, 3H) (one NH proton and one CO.sub.2H proton missing) A210 (400 MHz, D.sub.2O) 9.93 (d, 1H) 9.83 (d, 1H) 8.90 (dd, 1H) 8.03 (d, 1H) 7.53 (d, 1H) 7.30 (d, 1H) 5.23-5.15 (m, 2H) 3.29 (t, 2H) (two NH protons and one CO.sub.2H proton missing) A211 0 (400 MHz, D.sub.2O) 10.24 (dd, 1H) 9.87 (dd, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 4.99 (t, 2H) 4.08 (t, 1H) 2.23- 2.44 (m, 2H) 2.00-2.16 (m, 2H) (three NH protons and one CO.sub.2H proton missing) A212 .sup.1H NMR (400 MHz, D.sub.2O) 10.00 (d, 1H) 9.08 (d, 1H) 9.00 (d, 2H) 7.65 (t, 1H) 5.16 (t, 2H) 3.68 (t, 2H) 3.12 (s, 3H) A213 (400 MHz, D.sub.2O) 10.13 (d, 1H) 9.86 (d, 1H) 9.35 (dd, 1H) 9.11 (dd, 1H) 8.57 (dd, 1H) 8.05 (dd, 1H) 5.27-5.21 (m, 2H) 3.71-3.64 (m, 2H) (one NH proton missing) A214 (400 MHz, d.sub.6-DMSO) 10.36 (s, 1H) 10.06-10.10 (m, 1H) 9.56-9.62 (m, 1H) 9.18-9.22 (m, 2H) 7.82-7.86 (m, 1H) 5.88-5.94 (m, 2H) 2.80-2.86 (m, 6H) A215 (400 MHz, D.sub.2O) 10.18 (s, 1H) 9.78- 9.82 (m, 1H) 9.16-9.20 (m, 1H) 8.96- 9.02 (m, 2H) 7.62-7.66 (m, 1H) 4.86- 4.94 (m, 2H) 2.88-2.94 (m, 2H) 2.18- 2.28 (m, 2H) 1.72-1.82 (m, 2H) A216 (400 MHz, D.sub.2O) 10.16 (s, 1H) 9.80 (d, 1H) 9.14-9.20 (m, 1H) 8.96-9.00 (m, 2H) 7.60-7.66 (m, 1H) 4.96-5.04 (m, 2H) 4.06-4.12 (m, 2H) 2.44-2.52 (m, 2H) A217 (400 MHz, D.sub.2O) 10.16 (s, 1H) 9.78- 9.82 (m, 1H) 9.16-9.20 (m, 1H) 8.96- 9.00 (m, 2H) 7.62-7.66 (m, 1H) 4.88- 4.94 (m, 2H) 3.16 (s, 3H) 2.52-2.58 (m, 2H) 2.36-2.42 (m, 2H) A218 (400 MHz, D.sub.2O) 10.18 (s, 1H) 9.82- 9.86 (m, 1H) 9.18-9.24 (m, 1H) 8.98- 9.02 (m, 2H) 7.64-7.68 (m, 1H) 5.12- 5.18 (m, 2H) 3.60 (s, 3H) 3.00-3.04 (m, 2H) A219 (400 MHz, D.sub.2O) 10.22 (s, 1H) 9.84- 9.88 (m, 1H) 9.28-9.32 (m, 1H) 8.99- 9.04 (m, 2H) 7.64-7.68 (m, 1H) 5.64- 5.68 (m, 2H) 3.72 (s, 3H) A220 (400 MHz, D.sub.2O) 10.18 (s, 1H) 9.81 (d, 1H) 9.18-9.22 (m, 1H) 8.98-9.02 (m, 2H) 7.64-7.68 (m, 1H) 4.90-4.96 (m, 2H) 2.50-2.56 (m, 2H) 2.34-2.42 (m, 2H) A221 00 (400 MHz, D.sub.2O) 10.18 (s, 1H) 9.68- 9.76 (m, 1H) 9.18-9.22 (m, 1H) 9.00- 9.06 (m, 2H) 7.64-7.70 (m, 1H) 4.96- 5.04 (d, 1H) 4.60-4.68 (m, 1H) 3.82- 3.92 (m, 1H) 1.36 (d, 3H) (one NH proton missing) A222 01 (400 MHz, D.sub.2O) 10.12 (s, 1H) 9.62- 9.68 (m, 1H) 9.12-9.18 (m, 1H) 8.94- 9.02 (m, 2H) 7.60-7.66 (m, 1H) 4.94 (d, 1H) 4.58-4.66 (m, 1H) 4.04-4.14 (m, 1H) 3.16-3.28 (m, 2H) 2.04-2.18 (m, 1H) 1.72-1.98 (m, 3H) A223 02 (400 MHz, D.sub.2O) 10.18 (s, 1H) 9.68- 9.74 (m, 1H) 9.14-9.18 (m, 1H) 8.96- 9.02 (m, 2H) 7.62-7.66 (m, 1H) 5.14- 5.24 (m, 1H) 3.38-3.54 (m, 2H) 1.68 (d, 3H) (one NH proton missing) A224 03 (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.85 (dd, 1H) 9.41-9.44 (m, 1H) 9.21 (dd, 1H) 9.11 (d, 1H) 8.36 (dd, 1H) 5.26 (dd, 1H) 4.97 (dd, 1H) 4.71-4.78 (m, 1H) 3.21- 3.37 (m, 2H) (one OH proton missing) A225 04 (400 MHz, D.sub.2O) 10.14-10.18 (m, 1H) 9.64-9.68 (m, 1H) 9.16-9.22 (m, 1H) 8.96-9.00 (m, 2H) 7.60-7.64 (m, 1H) 4.82-4.88 (m, 2H) 3.58-3.64 (m, 2H) A226 05 (400 MHz, D.sub.2O) 10.16 (s, 1H) 9.86 (d, 1H) 9.16-9.20 (m, 1H) 8.96-9.02 (m, 2H) 7.60-7.66 (m, 1H) 5.08-5.14 (m, 2H) 3.20-3.28 (m, 2H) A227 06 (400 MHz, D.sub.2O) 10.18 (s, 1H) 10.00- 10.04 (m, 1H) 9.26-9.30 (m, 1H) 8.96- 9.02 (m, 2H) 7.62-7.66 (m, 1H) 6.42- 6.48 (m, 2H) A228 07 (400 MHz, CD.sub.3OD) 10.44-10.30 (m, 1H) 10.12-10.05 (m, 1H) 9.42 (dd, 1H) 9.10 (d, 2H) 8.10 (d, 2H) 7.74-7.67 (m, 3H) 6.19 (s, 2H) A229 08 (400 MHz, CD.sub.3OD) 10.40-10.35 (m, 1H) 10.10-10.05 (m, 1H) 9.43 (dd, 1H) 9.11 (d, 2H) 8.14-8.08 (m, 2H) 7.75-7.68 (m, 3H) 6.18 (s, 2H) 3.91 (s, 3H) A230 09 (400 MHz, d.sub.6-DMSO) 10.39-10.35 (m, 1H) 10.01 (d, 1H) 9.47 (dd, 1H) 9.22 (d, 2H) 7.84 (t, 1H) 5.78 (d, 2H) 4.24-4.13 (m, 4H) 1.27 (t, 6H) A231 0 (400 MHz, D.sub.2O) 10.04-9.99 (m, 1H) 9.85 (d, 1H) 9.05 (dd, 1H) 8.03 (s, 1H) 5.23 (t, 2H) 3.66 (t, 2H) 2.71 (s, 3H) 2.59 (s, 3H) A232 (400 MHz, D.sub.2O) 10.24 (dd, 1H) 9.86 (dd, 1H) 9.26 (dd, 1H) 9.06 (d, 2H) 7.71 (t, 1H) 4.98 (t, 2H) 3.92 (quin, 2H) 2.37 (ddd, 2H) 1.69-1.80 (m, 2H) 1.23 (t, 3H) (one POH proton missing) A233 (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.84 (d, 1H) 9.23 (dd, 1H) 9.03 (d, 2H) 7.68 (t, 1H) 4.97 (t, 2H) 2.33-2.46 (m, 2H) 1.77- 1.89 (m, 2H) (two OH protons missing) A234 (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.36 (br d, 1H) 9.10 (dd, 1H) 8.48- 8.56 (m, 1H) 7.92-8.07 (m, 1H) 4.98- 5.20 (m, 2H) 3.18-3.32 (m, 2H) (one CO.sub.2H proton missing) A235 (400 MHz, D.sub.2O) 10.14 (d, 1H) 9.92 (d, 1H) 9.42 (d, 1H) 9.18 (dd, 1H) 9.10 (d, 1H) 8.35 (dd, 1H) 5.09-5.21 (m, 2H) 3.87 (dd, 1H) 2.72 (dd, 2H) (three NH protons and one CO2H proton missing) [Note: pentafluoropropionic acid was used in the HPLC eluent instead of trifluoroacetic acid] A236 (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.74- 9.69 (m, 1H) 9.34 (s, 1H) 9.14-9.09 (m, 1H) 9.04-9.00 (m, 1H) 8.30-8.26 (m, 1H) 5.11 (d, 2H) (one POH proton missing) A237 (400 MHz, D.sub.2O) 10.19-10.13 (m, 1H) 9.93-9.87 (m, 1H) 9.43-9.38 (m, 1H) 9.27-9.22 (m, 1H) 9.11-9.05 (m, 1H) 8.34 (dd, 1H) 5.72-5.65 (m, 2H) 3.90- 3.84 (m, 6H) A238 (400 MHz, D.sub.2O) 10.37 (d, 1H) 10.00 (d, 1H) 9.48-9.42 (m, 1H) 9.23-9.20 (m, 2H) 7.83 (t, 1H) 5.82 (d, 2H) 3.83 (s, 3H) 3.82-3.78 (m, 3H) A239 (400 MHz, D.sub.2O) 10.09 (d, 1H) 9.86 (d, 1H) 9.40-9.35 (m, 1H) 9.13 (dd, 1H) 9.06 (d, 1H) 8.31 (dd, 1H) 5.11-4.98 (m, 2H) 3.88-3.76 (m, 2H) 2.44 (td, 2H) 1.11 (t, 3H) A240 (400 MHz, D.sub.2O) 10.10-10.06 (m, 1H) 9.89-9.85 (m, 1H) 9.39-9.36 (m, 1H) 9.15-9.10 (m, 1H) 9.07-9.04 (m, 1H) 8.33-8.28 (m, 1H) 5.11-5.02 (m, 2H) 2.51-2.40 (m, 2H) (one OH proton missing) A241 0 (400 MHz, D.sub.2O) 10.11-10.08 (m, 1H) 9.80-9.75 (m, 1H) 9.41-9.38 (m, 1H) 9.20-9.15 (m, 1H) 9.10-9.06 (m, 1H) 8.36-8.31 (m, 1H) 5.26-5.20 (m, 2H) 3.67-3.61 (m, 3H) A242 (400 MHz, D.sub.2O) 10.02-9.98 (m, 1H) 9.71-9.64 (m, 1H) 9.33-9.28 (m, 1H) 9.11-9.06 (m, 1H) 9.01-8.96 (m, 1H) 8.26-8.21 (m, 1H) 5.15-5.08 (m, 2H) 3.94-3.84 (m, 2H) 1.12 (t, 3H) A243 (400 MHz, D.sub.2O) 10.14-10.11 (m, 1H) 9.92-9.88 (m, 1H) 9.37 (d, 1H) 9.19- 9.14 (m, 1H) 9.05 (d, 1H) 8.32-8.28 (m, 1H) 5.20-5.10 (m, 2H) 4.12-4.02 (m, 4H) 2.88-2.76 (m, 2H) 1.18 (t, 6H) A244 (400 MHz, D.sub.2O) 10.17-10.13 (m, 1H) 9.91-9.85 (m, 1H) 9.40-9.36 (m, 1H) 9.25-9.19 (m, 1H) 9.08-9.04 (m, 1H) 8.34-8.29 (m, 1H) 5.66-5.58 (m, 2H) 4.32-4.14 (m, 4H) 1.25 (br t, 6H) A245 (400 MHz, D.sub.2O) 10.19-10.15 (m, 1H) 9.73-9.69 (m, 1H) 9.25-9.20 (m, 1H) 9.01 (d, 2H) 7.68-7.62 (m, 1H) 5.19 (d, 2H) 3.61 (d, 3H) A246 (400 MHz, D.sub.2O) 10.20 (d, 1H) 10.00 (dd, 1H) 9.45 (d, 1H) 9.28 (dd, 1H) 9.13 (d, 1H) 8.39 (dd, 1H) 6.15 (d, 1H) 3.82 (s, 3H) 2.05 (d, 3H) A247 (400 MHz, D.sub.2O) 10.11-10.05 (m, 1H) 9.88-9.83 (m, 1H) 9.39-9.35 (m, 1H) 9.15-9.09 (m, 1H) 9.07-9.03 (m, 1H) 8.32-8.27 (m, 1H) 7.61-7.56 (m, 2H) 7.30-7.25 (m, 2H) 5.09-4.97 (m, 2H) 3.45 (d, 3H) 2.52-2.39 (m, 2H) 2.30 (s, (one POH proton missing) A248 (400 MHz, D.sub.2O) 10.18 (d, 1H) 9.81 (d, 1H) 9.19 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.07-4.97 (m, 2H) 3.46 (d, 3H) 2.53-2.42 (m, 2H) A249 (400 MHz, D.sub.2O) 10.16-10.13 (m, 1H) 9.94-9.90 (m, 1H) 9.42-9.39 (m, 1H) 9.21-9.16 (m, 1H) 9.11-9.07 (m, 1H) 8.36-8.31 (m, 1H) 5.23-5.13 (m, 2H) 3.76-3.70 (m, 6H) 2.93-2.81 (m, 2H) A250 (400 MHz, D.sub.2O) 10.16-10.11 (m, 1H) 9.91-9.86 (m, 1H) 9.41-9.37 (m, 1H) 9.26-9.21 (m, 1H) 9.10-9.05 (m, 1H) 8.37-8.30 (m, 1H) 5.87 (s, 2H) 3.80 (s, 3H) A251 0 (400 MHz, D.sub.2O) 10.16 (s, 1H) 9.70 (br d, 1H) 9.24-9.18 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.15 (br d, 2H) 3.99-3.89 (m, 2H) 1.17 (t, 3H)

BIOLOGICAL EXAMPLES

(385) Post-Emergence Efficacy

(386) Method A

(387) Seeds of a variety of test species were sown in standard soil in pots. After cultivation for 14 days (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the dissolution of the technical active ingredient formula (I) in a small amount of acetone and a special solvent and emulsifier mixture referred to as IF50 (11.12% Emulsogen EL360 TM+44.44% N-methylpyrrolidone+44.44% Dowanol DPM glycol ether), to create a 50 g/l solution which was then diluted to required concentration using 0.25% or 1% Empicol ESC70 (Sodium lauryl ether sulphate)+1% ammonium sulphate as diluent.

(388) The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days the test was evaluated (100=total damage to plant; 0=no damage to plant).

(389) The results are shown in Table B (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.

(390) Test Plants:

(391) Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)

(392) TABLE-US-00012 TABLE B Control of weed species by compounds of Formula (I) after post-emergence application Compound Application Number Rate g/Ha AMAPA CHEAL EPHHL IPOHE SETFA ECHCG ELEIN DIGSA LOLPE A1 500 100 100 100 100 100 70 100 100 70 A2 500 60 20 90 10 80 50 30 40 0 A4 500 100 80 100 90 60 60 100 80 100 A5 500 100 100 100 40 90 100 100 100 100 A6 500 100 100 100 60 100 80 100 100 60 A7 500 100 100 100 60 90 80 100 100 60 A8 500 10 10 10 10 20 10 20 20 0 A9 500 100 100 70 30 60 100 100 100 80 A10 500 100 100 100 40 60 30 50 60 90 A11 500 100 100 100 100 30 60 100 80 80 A12 500 100 100 40 30 70 80 100 100 90 A13 500 100 50 70 50 60 50 100 70 50 A14 500 80 60 20 40 60 60 90 90 40 A15 500 n/a 90 20 10 50 40 80 60 10 A16 500 60 30 50 40 50 60 70 50 10 A17 500 100 30 30 30 40 40 60 60 10 A18 500 n/a 0 10 10 40 30 60 50 10 A19 500 100 60 60 40 60 40 60 50 20 A20 500 n/a 100 80 40 100 100 100 100 60 A21 500 100 80 80 40 90 60 100 90 80 A22 500 n/a 100 70 30 100 100 100 100 80 A23 500 n/a 80 90 60 100 70 100 80 70 A24 500 90 70 80 70 70 60 40 40 60 A25 500 100 60 40 50 60 70 50 50 40 A26 500 n/a 100 100 40 100 100 100 100 90 A28 500 100 100 100 100 100 90 100 90 70 A29 500 100 100 100 20 90 90 90 100 50 A30 500 100 90 100 80 100 80 100 100 70 A31 500 100 100 50 100 50 60 80 90 60 A32 500 n/a 70 70 40 80 70 100 90 30 A33 500 100 80 60 40 60 40 80 60 50 A34 500 100 70 70 70 70 30 90 60 60 A35 500 100 100 100 n/a 100 80 90 100 90 A36 500 100 90 90 30 100 90 100 90 80 A37 500 n/a 100 80 30 100 100 100 100 80 A38 500 100 50 30 20 70 30 70 100 40 A39 500 100 90 90 0 40 30 80 70 60 A40 500 90 70 90 100 100 90 90 90 90 A41 500 n/a 90 90 30 100 100 100 100 70 A42 500 50 0 30 20 50 30 20 50 0 A43 500 n/a 90 80 30 100 70 100 90 20 A44 500 40 10 20 20 60 30 20 40 20 A45 500 n/a 60 50 20 100 90 80 80 30 A46 500 70 10 60 10 50 30 50 50 20 A47 500 n/a 100 80 50 100 70 100 100 60 A48 500 n/a 100 90 20 100 70 100 90 70 A49 500 100 80 70 60 100 60 100 90 50 A50 500 100 20 90 50 60 40 90 50 60 A51 500 n/a 70 30 20 70 60 90 90 60 A52 500 n/a 60 60 20 70 60 70 70 10 A53 500 n/a 100 80 70 80 70 70 80 40 A54 500 90 90 70 10 100 90 100 100 70 A55 500 n/a 80 70 70 100 90 100 100 60 A56 500 90 90 100 30 100 80 100 100 40 A57 500 n/a 60 60 10 60 40 40 80 10 A58 500 100 80 60 10 90 60 80 90 50 A59 500 90 90 100 80 100 80 90 100 70 A60 500 n/a 100 70 60 90 90 100 100 70 A61 500 n/a 80 90 50 100 90 100 100 70 A62 500 n/a 100 100 60 100 70 90 100 30 A63 500 40 30 30 20 40 40 50 30 20 A64 500 90 90 100 20 90 60 100 80 80 A65 500 40 10 20 10 40 30 40 30 10 A66 500 40 20 50 40 60 50 40 30 50 A67 500 60 50 80 20 70 80 70 60 40 A68 500 60 70 100 50 60 70 70 40 60 A69 500 100 60 50 40 40 40 60 50 50 A70 500 90 70 50 20 30 30 20 30 20 A71 500 100 60 40 40 30 30 30 30 10 A72 500 60 40 70 40 40 40 30 30 20 A73 500 40 30 60 30 60 60 60 30 40 A74 500 60 30 60 50 80 60 80 50 60 A75 500 60 30 60 20 70 50 60 50 50 A76 500 30 20 30 20 40 30 30 20 30 A77 500 100 80 80 30 100 90 100 100 80 A78 500 0 10 20 20 40 30 30 40 20 A79 500 10 30 10 0 10 10 20 20 0 A81 500 100 90 100 40 90 90 80 100 40 A82 500 70 80 40 20 60 30 60 30 0 A83 500 90 80 90 40 90 50 100 100 70 A84 500 100 80 90 30 50 20 20 50 30 A85 500 90 90 100 30 90 70 90 90 70 A86 500 30 40 50 40 40 20 10 30 10 A87 500 50 30 50 40 70 70 60 70 70 A88 500 100 70 60 30 70 60 90 90 60 A89 500 100 40 100 70 70 60 40 50 40 A90 500 40 20 60 30 30 20 20 30 20 A91 500 40 20 40 20 60 60 60 50 20 A92 500 90 90 70 100 90 80 90 60 50 A93 500 90 80 40 20 100 80 100 100 80 A94 500 70 90 40 30 40 30 20 30 20 A95 500 30 40 40 30 50 50 30 40 20 A96 500 70 20 90 40 70 70 40 40 60 A97 500 90 20 70 30 90 90 90 90 70 A98 500 40 20 40 30 20 20 20 10 0 A99 500 80 30 90 30 50 50 80 40 20 A100 500 60 60 90 20 20 70 60 40 10 A101 500 80 70 80 10 80 60 40 60 70 A102 500 20 50 20 0 10 10 10 10 10 A103 500 0 50 50 30 10 30 30 20 10 A104 500 10 0 20 30 30 30 50 30 10 A105 500 90 20 50 0 90 40 20 60 50 A106 500 80 20 20 10 60 50 80 60 60 A107 500 100 100 100 100 100 100 100 100 70 A108 500 40 80 80 70 60 40 60 50 40 A109 500 60 60 60 50 30 40 50 50 30 A110 500 100 100 80 80 50 50 90 40 50 A112 500 100 100 80 40 70 40 50 40 40 A113 500 40 90 100 60 50 60 40 60 10 A114 500 100 60 80 60 40 60 90 80 70 A115 500 100 100 30 40 60 50 30 30 30 A116 500 100 80 50 10 30 20 20 30 10 A117 500 90 90 100 80 100 90 90 70 50 A118 500 80 80 90 60 70 40 70 90 90 A119 500 100 100 70 50 40 30 30 40 30 A120 500 90 70 50 10 40 40 30 40 20 A121 500 100 80 80 20 30 40 20 40 30 A122 500 100 100 100 70 60 40 90 40 70 A123 500 100 80 100 100 100 90 100 100 60 A124 500 0 0 0 0 20 0 0 10 0 A125 500 100 80 100 30 100 100 100 100 90 A126 500 100 80 100 30 100 80 90 80 70 A127 500 10 20 20 10 30 40 20 80 10 A128 500 30 10 0 0 30 30 50 30 40 A129 500 70 50 70 10 60 90 40 60 80 A130 500 100 90 100 40 100 100 100 90 80 A131 500 100 70 40 50 100 100 100 90 30 A132 500 90 30 30 10 100 70 90 90 50 A133 500 60 40 20 20 90 70 90 70 40 A134 500 100 80 90 70 100 80 100 100 80 A135 500 60 20 50 30 50 50 70 30 60 A136 500 60 30 30 30 70 40 50 60 20 A137 500 60 20 20 10 40 30 40 40 20 A138 500 100 100 100 30 100 100 80 100 100 A139 500 80 100 90 10 100 100 100 100 90 A140 500 60 50 50 20 30 20 10 10 0 A141 500 100 60 20 30 50 50 60 40 30 A142 500 10 20 60 20 30 40 60 40 10 A143 500 100 90 80 30 100 100 100 90 70 A144 500 20 10 20 10 20 20 20 30 10 A145 500 10 10 10 10 0 0 0 10 0 A146 500 90 40 50 30 100 90 80 80 50 A147 500 40 50 70 60 40 30 20 20 40 A148 500 100 40 60 20 50 50 40 50 20 A149 500 30 40 30 10 40 50 60 50 40 A151 500 20 20 40 10 20 20 20 20 10 A152 500 20 10 20 0 20 20 20 30 10 A153 500 90 60 40 20 20 40 20 20 0 A154 125 40 50 70 20 30 20 10 20 10 A155 500 20 10 30 20 40 40 30 50 50 A156 500 30 50 50 10 20 10 20 20 0 A157 500 100 100 80 60 80 80 90 70 30 A158 500 100 80 80 30 40 20 50 30 30 A159 500 100 100 80 50 60 70 50 30 40 A160 500 100 100 90 70 90 70 80 70 70 A161 500 30 70 50 20 10 20 20 20 10 A162 500 100 70 80 10 70 90 80 70 90 A163 500 100 60 50 30 n/a 40 90 50 70 A164 500 100 80 90 40 50 30 80 30 40 A165 500 100 50 50 40 60 70 70 60 60 A166 500 30 50 60 60 40 50 60 70 70 A167 500 20 70 90 100 40 60 80 50 40 A168 500 0 40 30 20 10 20 20 10 10 A169 500 100 70 n/a 40 50 40 90 50 50 A170 500 100 100 70 40 80 80 40 40 50 A171 500 100 80 n/a 80 60 60 80 60 70 A172 500 30 60 50 40 50 50 70 80 20 A173 500 30 50 40 20 30 30 10 20 10 A174 500 100 40 60 50 60 50 60 50 60 A175 500 30 60 30 20 30 30 40 40 10 A176 500 40 30 n/a 40 40 30 70 30 40 A177 500 60 50 30 20 0 0 10 10 0 A178 500 90 70 40 20 10 10 0 10 0 A179 500 30 30 60 20 60 40 50 50 10 A180 500 100 90 80 20 70 70 90 60 30 A181 500 90 90 n/a 80 60 100 100 80 90 A183 500 10 0 n/a 20 10 20 10 30 10 A185 500 100 80 n/a 30 50 40 30 30 30 A186 500 70 70 30 30 60 30 50 60 10 A187 500 50 40 50 20 10 20 10 20 10 A188 500 90 50 30 20 30 50 20 40 20 A189 500 100 100 90 70 70 80 90 50 30 A190 500 100 80 80 70 40 60 70 60 40 A191 500 100 30 30 30 20 10 30 20 30 A192 500 90 60 40 30 20 30 30 30 10 A193 500 70 60 60 30 10 10 30 30 10 A194 500 100 70 70 60 50 70 90 50 50 A195 500 n/a 60 n/a 20 n/a 10 10 20 0 A196 500 30 40 30 20 0 0 10 0 0 A197 500 100 10 10 10 0 0 10 20 0 A198 500 100 100 100 50 90 80 80 80 50 A199 500 n/a 40 n/a 10 30 20 10 50 0 A200 500 100 70 70 10 50 40 30 40 40 A201 500 100 100 90 40 80 70 100 80 30 A202 500 100 90 100 60 70 80 20 60 70 A203 500 100 90 50 20 60 50 60 70 0 A204 500 10 20 0 0 0 0 0 0 0 A205 500 80 60 n/a 80 80 60 60 80 40 A206 500 60 90 60 20 10 20 10 20 0 A207 500 100 100 90 90 100 60 100 90 20 A208 500 100 80 50 20 60 30 60 40 10 A209 125 30 10 0 0 20 10 0 30 10 A210 500 70 10 10 10 30 10 20 60 20 A211 500 100 100 100 60 100 100 90 100 60 A212 500 100 100 100 30 80 70 90 90 70 A213 500 100 90 100 70 100 100 100 100 90 A214 500 100 100 100 40 90 100 100 100 80 A215 500 100 60 90 60 20 30 30 60 20 A216 500 100 90 100 60 90 70 100 100 70 A218 500 100 80 80 70 60 60 60 70 70 A219 500 100 80 90 60 90 40 100 70 70 A220 500 100 100 90 80 60 40 20 90 60 A221 500 100 90 90 60 80 60 100 100 60 A222 500 80 60 n/a 70 80 70 60 90 20 A223 500 100 90 80 60 80 70 90 90 80 A224 500 100 90 n/a 80 40 40 80 80 40 A225 500 100 90 100 70 30 30 90 60 30 A226 500 100 100 100 50 90 90 100 100 90 A228 500 80 60 n/a 60 10 10 10 20 0 A229 500 10 0 n/a 10 10 0 0 20 0 A230 500 50 60 n/a 20 50 60 10 70 0 A231 500 100 90 n/a 60 60 50 60 80 60 A232 500 100 90 n/a 0 80 100 50 90 20 A233 500 100 100 n/a 70 70 60 50 60 20 A234 500 100 100 100 60 100 100 100 100 90 A235 500 10 40 20 20 30 30 10 40 0 A236 500 90 20 30 40 30 50 10 80 0 A237 500 60 10 0 50 20 10 70 50 10 A238 500 50 20 50 40 50 40 30 50 10

(393) Method B

(394) An “instant formulation”, known as the IF50, containing 50 g/L of the “technical” (i.e. unformulated) active ingredient was prepared by dissolving the active ingredient in a mixture of organic solvents and emulsifier, details of which are provided in the table. This IF50 was then mixed with a small, variable amount of acetone to aid dissolution, before addition of an aqueous solution of 1% v/v ammonium sulphate+1% v/v Empicol ESC70 (Sodium lauryl ether sulphate) adjuvant, as the aqueous diluent, to form an aqueous spray solution which contains a predetermined concentration of the active ingredient (which varies depending on the application rate of the active ingredient to the plants).

(395) Composition of the mixture of organic solvents and emulsifier used as a base for the instant formulation.

(396) TABLE-US-00013 Chemical CAS Registry Amount/ Component Supplier description number % w/w Emulsogen EL360 ™ Clariant Castor oil ethoxylate 61791-12-6 10.6 N-methylpyrrolidone Widely 1-Methyl-2-pyrrolidone 872-50-4 42.2 available Dowanol DPM Dow Dipropylene glycol 34590-94-8 42.2 glycol ether monomethyl ether

(397) This aqueous spray solution was then sprayed onto the plants, after about 12 days' cultivation. The plants were grown from seeds sown in standard soil, placed in a glasshouse under controlled conditions (at 24/18° C. or 20/16° C., day/night; 16 hours light; 65% humidity). After spray application the plants were then grown on in a glasshouse under the same conditions and watered twice daily. After 15 days the test was evaluated (100=total damage to plant; 0=no damage to plant).

(398) The results are shown in Table C (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.

(399) Test Plants:

(400) Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), 20 Amaranthus retroflexus (AMARE), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)

(401) TABLE-US-00014 TABLE C Control of weed species by compounds of Formula (I) after post-emergence application Compound Application Number Rate g/Ha AMARE CHEAL EPHHL IPOHE SETFA ECHCG ELEIN DIGSA LOLPE A4 500 100 80 100 100 40 70 80 100 90 A28 1000 100 90 100 100 40 100 100 100 70 A41 1000 100 90 100 20 100 100 50 100 60 A138 1000 100 100 100 40 100 100 100 100 100 A207 1000 100 90 70 100 100 100 100 90 20 A211 500 100 90 80 100 100 100 100 100 10 A213 1000 100 80 100 80 100 100 100 100 90 A220 1000 100 90 100 30 30 90 100 100 90 A226 1000 100 100 n/a 100 70 100 n/a 100 70

(402) Method C

(403) An “instant formulation”, known as the IF50, containing 50 g/L of the “technical” (i.e. unformulated) active ingredient was prepared by dissolving the active ingredient in a mixture of organic solvents and emulsifier, details of which are provided in the table. This IF50 was then mixed with a small, variable amount of acetone to aid dissolution, before addition of a 1% v/v aqueous solution of the adjuvant Empicol ESC70 3EO (Sodium lauryl ether sulphate) and 1% v/v Ammonium sulphate, as the aqueous diluent, to form an aqueous spray solution which contains a predetermined concentration of the active ingredient (which varies depending on the application rate of the active ingredient to the plants).

(404) Composition of the mixture of organic solvents and emulsifier used as a base for the instant formulation.

(405) TABLE-US-00015 Chemical CAS Registry Amount/ Component Supplier description number % w/w Emulsogen EL360 ™ Clariant Castor oil ethoxylate 61791-12-6 10.6 N-methylpyrrolidone Widely 1-Methyl-2-pyrrolidone 872-50-4 42.2 available Dowanol DPM Dow Dipropylene glycol 34590-94-8 42.2 glycol ether monomethyl ether

(406) This aqueous spray solution was then sprayed onto the plants after about 21 days' cultivation. The plants were grown from seeds sown in standard soil, placed in a glasshouse under controlled conditions (at 24/18° C., day/night; 14 hours light; 65% humidity). After spray application the plants were then grown on in a glasshouse under the same conditions and watered twice daily. The test was evaluated at 21 days (100=total damage to plant; 0=no damage to plant).

(407) The results are shown in Table D (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.

(408) Test Plants:

(409) Ipomoea hederacea (IPOHE), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Conyza canadensis (ERICA)

(410) TABLE-US-00016 TABLE D Control of weed species by compounds of Formula (I) after post-emergence application Compound Application Number Rate g/Ha AMAPA IPOHE ECHCG ELEIN LOLPE ERICA A3 400 65 83 13 15 25 100 A27 400 77 90 43 80 68 65